Pyrrole[2,3-b]pyridine derivatives active as kinase inhibitors

ABSTRACT

Compounds which are pyrrolo[2,3-b]pyridine derivatives or pharmaceutically acceptable salts thereof, their preparation process and pharmaceutical compositions comprising them are disclosed; these compounds are useful in the treatment of diseases caused by and/or associated with an altered protein kinase activity such as cancer, cell proliferative disorders, Alzheimer&#39;s disease, viral infections, auto-immune diseases and neurodegenerative disorders; also disclosed is a process under SPS conditions for preparing the compounds of the invention and chemical libraries comprising a plurality of them.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of copending application Ser.No. 11/020,794 filed Dec. 23, 2004, which claims benefit of BritishPatent Application No. 0330042.3 filed Dec. 24, 2003, the entirecontents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pyrrolo[2,3-b]pyridine derivativesactive as kinase inhibitors and, more in particular, it relates topyrrolo[2,3-b]pyridine derivatives further substituted in position 5, toa process for their preparation, to combinatorial libraries thereof, topharmaceutical compositions comprising them and to their use astherapeutic agents, particularly in the treatment of diseases linked todisregulated protein kinases.

2. Discussion of the Background

The malfunctioning of protein kinases (PKs) is the hallmark of numerousdiseases. A large share of the oncogenes and proto-oncogenes involved inhuman cancers code for PKs. The enhanced activities of PKs are alsoimplicated in many non-malignant diseases, such as benign prostatehyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis andpost-surgical stenosis and restenosis.

PKs are also implicated in inflammatory conditions and in themultiplication of viruses and parasites. PKs may also play a major rolein the pathogenesis and development of neurodegenerative disorders.

For a general reference to PKs malfunctioning or disregulation see, forinstance, Current Opinion in Chemical Biology 1999, 3, 459-465.

SUMMARY OF THE INVENTION

It is an object of the invention to provide compounds that are useful intherapy as agents against a host of diseases caused by and/or associatedto a disregulated protein kinase activity.

It is another object to provide compounds that are endowed with proteinkinase inhibiting activity.

The present inventors have now discovered that somepyrrolo[2,3-b]pyridine derivatives are endowed with protein kinaseinhibiting activity and may be thus useful in therapy in the treatmentof diseases associated with disregulated protein kinases.

More specifically, the compounds of this invention are useful in thetreatment of a variety of cancers including, but not limited to:carcinoma such as bladder, breast, colon, kidney, liver, lung, includingsmall cell lung cancer, esophagus, gall-bladder, ovary, pancreas,stomach, cervix, thyroid, prostate, and skin, including squamous cellcarcinoma; hematopoietic tumours of lymphoid lineage, includingleukemia, acute lymphocite leukemia, acute lymphoblastic leukemia,B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin'slymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietictumours of myeloid lineage, including acute and chronic myelogenousleukemias, myelodysplastic syndrome and promyelocytic leukemia; tumoursof mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;tumours of the central and peripheral nervous system, includingastrocytoma, neuroblastoma, glioma and schwannomas; other tumours,including melanoma, seminoma, teratocarcinoma, osteosarcoma, xerodermapigmentosum, keratoxanthoma, thyroid follicular cancer and Kaposi'ssarcoma.

Due to the key role of PKs in the regulation of cellular proliferation,these pyrrolo[2,3-b]pyridine compounds are also useful in the treatmentof a variety of cell proliferative disorders such as, for instance,benign prostate hyperplasia, familial adenomatosis, polyposis,neuro-fibromatosis, psoriasis, vascular smooth cell proliferationassociated with atherosclerosis, pulmonary fibrosis, arthritisglomerulonephritis and post-surgical stenosis and restenosis.

The compounds of the invention are, in addition, useful in the treatmentof Alzheimer's disease, as suggested by the fact that cdk5 is involvedin the phosphorylation of tau protein (J. Biochem., 117, 741-749, 1995).

The compounds of this invention, as modulators of apoptosis, are usefulin the treatment of cancer, viral infections, prevention of AIDSdevelopment in HIV-infected individuals, autoimmune diseases andneurodegenerative disorders.

The compounds of this invention are useful in inhibiting tumourangiogenesis and metastasis, as well as in the treatment of organtransplant rejection and host versus graft disease.

The compounds of the invention also act as inhibitor of other proteinkinases, e.g., cyclin-dependent kinases (cdk) such as cdk2 and cdk5,protein kinase C in different isoforms, Met, PAK-4, PAK-5, ZC-1, STLK-2,DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chk1, Chk2, HER2, raf1, MEK1,MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, PI3K, weel kinase, Src, Abl, Akt,MAPK, ILK, MK-2, IKK-2, Cdc7, Nek, and thus be effective in thetreatment of diseases associated with other protein kinases.

The compounds of the invention are also useful in the treatment andprevention of radiotherapy-induced or chemotherapy-induced alopecia.

DETAILED DESCRIPTION OF THE INVENTION

Pyrrolo-pyridine derivatives are widely known in the art. As an example,the compound 3-carboxamido-pyrrolo[2,3-b]pyridine is reported assynthetic intermediate in Chemical Abstracts C.A. 93 (1980):168162.

Some other 3-carboxamido derivatives of pyrrolo-pyridine furtherN-substituted by indolyl groups are disclosed as 5-HT2C/2B antagonists(see WO 96/11929); the above 3-carboxamido derivatives furthersubstituted by N-(isoquinolyl-ethyl-cyclohexyl) groups are disclosed asantipsychotic agents (see WO 00/24717; WO 00/21951; WO 00/21950; WO98/50364); 3-carboxamido-pyrrolo-pyridine compounds N-substituted byazabicyclo rings are also disclosed as synthetic intermediates in thepreparation of tropyl derivatives, possessing antitussive properties.

Moreover, 3-hydrazido pyrrolo-pyridine derivatives are disclosed assynthetic intermediates for preparing more complex protein kinaseinhibitors, as reported in WO 00/71537.

7-Azaindoles as inhibitors of C-JUN N-terminal kinases and thus usefulin the treatment of neurodegenerative disorders are also disclosed in WO03/082868. However, none of the pyrrolo-pyridine derivatives of theprior art resulted to bear an additional amino group, optionally furtherfunctionalised, in position 5 of the pyrrolo-pyridine skeleton.

Broad general formula pyrrolo[2,3-b]pyridine compounds endowed withtherapeutic activity, also including protein kinase inhibitory activity,are also disclosed in WO 00/71537; WO 01/01986; WO 01/58869; WO99/32111; WO 99/37637; WO 97/03069; WO 99/58496 and WO 95/28400.

3-Alkenyl-pyrrolo[2,3-b]pyridine derivatives as protein kinaseinhibitors are also disclosed in WO 01/98299 in the name of theApplicant itself.

Accordingly, the present invention provides a method for treatingdiseases caused by and/or associated with an altered protein kinaseactivity, by administering to a mammal in need thereof an effectiveamount of a compound represented by formula (I)

wherein

R is selected from the group consisting of —R^(a), —COR^(a),—CONR^(a)R^(b), —SO₂R^(a) or —COOR^(a);

R₁ is a group —NR^(c)R^(d) or —OR^(c);

wherein R^(a), R^(b), R^(c) and R^(d), the same or different, are eachindependently hydrogen or a group optionally further substituted,selected from straight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, carbocyclic orheterocyclic aryl or aryl C₁-C₆ alkyl, heterocycle or heterocycle C₁-C₆alkyl or, taken together with the nitrogen atom to which they arebonded, either R^(a) and R^(b) as well as R^(c) and R^(d) may form anoptionally substituted 4 to 7 membered heterocycle, optionallycontaining one additional heteroatom or heteroatomic group selected fromS, O, N or NH;

R₂ is a group, optionally further substituted, selected from straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, C₃-C₆ cycloalkylor cycloalkyl C₁-C₆ alkyl, carbocyclic or heterocyclic aryl or arylC₁-C₆ alkyl, heterocycle or heterocycle C₁-C₆ alkyl; or isomers,tautomers, carriers, metabolites, prodrugs, and pharmaceuticallyacceptable salts thereof.

In a preferred embodiment of the method described above, the diseasecaused by and/or associated with an altered protein kinase activity isselected from the group consisting of cancer, cell proliferativedisorders, Alzheimer's disease, viral infections, autoimmune diseasesand neurodegenerative disorders.

Specific types of cancer that may be treated include carcinoma, squamouscell carcinoma, hematopoietic tumours of myeloid or lymphoid lineage,tumours of mesenchymal origin, tumours of the central and peripheralnervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma,xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer andKaposi's sarcoma.

In another preferred embodiment of the method described above, the cellproliferative disorder is selected from the group consisting of benignprostate hyperplasia, familial adenomatosis polyposis,neuro-fibromatosis, psoriasis, vascular smooth cell proliferationassociated with atherosclerosis, pulmonary fibrosis, arthritisglomerulonephritis and post-surgical stenosis and restenosis.

The present invention further provides a compound represented by formula(I)

wherein

R is selected from the group consisting of —R^(a), —COR^(a),—CONR^(a)R^(b), —SO₂R^(a) or —COOR^(a);

R₁ is a group —NR^(c)R^(d) or —OR^(c);

wherein R^(a), R^(b), R^(c) and R^(d), the same or different, are eachindependently hydrogen or a group optionally further substituted,selected from straight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, carbocyclic orheterocyclic aryl or aryl C₁-C₆ alkyl, heterocycle or heterocycle C₁-C₆alkyl or, taken together with the nitrogen atom to which they arebonded, either R^(a) and R^(b) as well as R^(c) and R^(d) may form anoptionally substituted 4 to 7 membered heterocycle, optionallycontaining one additional heteroatom or heteroatomic group selected fromS, O, N or NH;

R₂ is a group, optionally further substituted, selected from straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, C₃-C₆ cycloalkylor cycloalkyl C₁-C₆ alkyl, carbocyclic or heterocyclic aryl or arylC₁-C₆ alkyl, heterocycle or heterocycle C₁-C₆ alkyl; or isomers,tautomers, carriers, metabolites, prodrugs, and pharmaceuticallyacceptable salts thereof.

Unless otherwise specified, when referring to the compounds of formula(I) per se as well as to any pharmaceutical composition thereof or toany therapeutic method of treatment comprising them, the presentinvention includes all of the hydrates, solvates, complexes, metabolitesand prodrugs of the compounds of this invention. Prodrugs are anycovalently bonded compounds, which release the active parent drugaccording to formula (I) in vivo.

If a chiral center or another form of an isomeric center is present in acompound of the present invention, all forms of such isomer or isomers,including enantiomers and diastereomers, are intended to be coveredherein. Compounds containing a chiral center may be used as a racemicmixture or as an enantiomerically enriched mixture, or the racemicmixture may be separated using well-known techniques and an individualenantiomer may be used alone. In cases wherein compounds may exist intautomeric forms, such as keto-enol tautomers, each tautomeric form iscontemplated as being included within this invention whether existing inequilibrium or predominantly in one form.

In the present description, unless otherwise indicated, with the termstraight or branched C₁-C₆ alkyl we intend any group such as, forinstance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

With the term straight or branched C₂-C₆ alkenyl or alkynyl we intendany of the unsaturated alkenyl or alkynyl groups with from 2 to 6 carbonatoms for instance including vinyl, allyl, 1-propenyl, isopropenyl, 1-,2- or 3-butenyl, pentenyl, hexenyl, ethynyl, 1- or 2-propynyl, butynyl,pentynyl, hexynyl, and the like.

With the term C₃-C₆ cycloalkyl we intend any 3 to 6 membered carbocyclicring such as, for instance, cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

Unless otherwise specified, with the term aryl we intend a mono- orbi-cyclic, either carbocycle as well as heterocycle, with 1 or 2 ringmoieties either fused or linked to each other by single bonds, whereinat least one of the carbocyclic or heterocyclic rings is aromatic; butit also includes 1 or 2 ring moieties, wherein all of the rings arearomatic. Unless otherwise specified, the said heterocycle is a 4 to 7membered ring with from 1 to 3 ring heteroatoms or heteroatomic groupsselected among N, NH, O and S.

Non limiting examples of aryl groups of the invention are, for instance,phenyl, indanyl, biphenyl, α- or β-naphthyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolyl, imidazolyl, imidazopyridyl,1,2-methylenedioxyphenyl, thiazolyl, isothiazolyl, pyrrolyl,pyrrolyl-phenyl, furyl, phenyl-furyl, benzotetrahydrofuranyl, oxazolyl,isoxazolyl, pyrazolyl, chromenyl, thienyl, benzothienyl, isoindolinyl,benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl,benzofurazanyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, and the like.

With the term heterocycle (e.g. heterocyclyl) or heterocyclic group wealso intend a 4 to 7 membered heterocycle, hence encompassing aromaticheterocyclic groups also known as heteroaryl groups and presentlyencompassed by the term aryl, as well as heterocycles being saturated orpartially unsaturated with from 1 to 3 ring heteroatoms or heteroatomicgroups selected among N, NH, O and S.

Examples of these 4 to 7 membered heterocyclic groups are, for instance,1,3-dioxolane, pyran, pyrrolidine, pyrroline, imidazoline,imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine,morpholine, tetrahydrofuran, hexamethyleneimine, 1,4-hexahydrodiazepine,azetidine, and the like.

When referring to the compounds of formula (I) wherein R is a group—CONR^(a)R^(b) and/or R₁ is a group —NR^(c)R^(d) and R^(a) and R^(b)and/or R^(c) and R^(d) are taken together with the nitrogen atom towhich they are bonded, they may also form an optionally substituted 4 to7 membered heterocycle optionally containing one additional ringheteroatom or heteroatomic group among S, O, N or NH.

According to the meanings provided to R^(a), R^(b), R^(d) and R₂, any ofthe above groups may be further optionally substituted in any of theirfree positions by one or more groups, for instance 1 to 6 groups,selected from: halogen, nitro, oxo groups (═O), carboxy, cyano, alkyl,polyfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl; aryl,heterocyclyl, amino groups and derivatives thereof such as, forinstance, alkylamino, dialkylamino, arylamino, diarylamino, ureido,alkylureido or arylureido; carbonylamino groups and derivatives thereofsuch as, for instance, formylamino, alkylcarbonylamino,alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino; hydroxygroups and derivatives thereof such as, for instance, alkoxy,polyfluorinated alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy,cycloalkenyloxy or alkylideneaminoxy; carbonyl groups and derivativesthereof such as, for instance, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl; sulfurated derivatives suchas, for instance, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl,alkylsulfinyl, arylsulfinyl, arylsulfonyloxy, aminosulfonyl,alkylaminosulfonyl or dialkylaminosulfonyl.

In their turn, whenever appropriate, each of the above substituents maybe further substituted by one or more of the aforementioned groups. Inthe present description, unless otherwise specified, with the termhalogen atom we intend a fluorine, chlorine, bromine or iodine atom.

With the term polyfluorinated alkyl or alkoxy we intend a straight orbranched C₁-C₆ alkyl or alkoxy group as above defined, wherein more thanone hydrogen atom is replaced by fluorine atoms such as, for instance,trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethyl,2,2,2-trifluoroethoxy, 1,2-difluoroethyl,1,1,1,3,3,3-hexafluoropropyl-2-yl, and the like.

From all of the above, it is clear to the skilled man that any groupwhich name has been identified as a composite name such as, forinstance, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, alkoxy,alkylthio, aryloxy, arylalkyloxy, alkylcarbonyloxy and the like, has tobe intended as conventionally construed from the parts to which itderives. So far, as an example, the terms heterocyclyl-alkyl andcycloalkyl-alkyl stand for a straight or branched alkyl group beingfurther substituted by a heterocyclic or cycloalkyl group, respectively,as above defined.

The term “pharmaceutically acceptable salts” embraces salts commonlyused to form alkali metal salts and to form addition salts of free acidsor free bases. The nature of the salt is not critical, provided that itis pharmaceutically acceptable. Suitable pharmaceutically acceptableacid addition salts of the compounds of the present invention may beprepared from an inorganic acid or from an organic acid. Examples ofsuch inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric,carbonic, sulfuric, and phosphoric acid. Appropriate organic acids maybe selected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which are formic, acetic, trifluoroacetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic,sulfanilic, stearic, cyclohexylaminosulfonic, algenic, hydroxybutyric,galactaric and galacturonic acid. Suitable pharmaceutically acceptablebase addition salts of the compounds of the present invention includemetallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc or organic salts made fromN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methyl-glucamine) and procaine. All ofthese salts may be prepared by conventional means from the correspondingcompounds of the present invention, for instance by reacting them withthe appropriate acid or base.

A first class of preferred compounds of the invention is represented bythe derivatives of formula (I) wherein R₁ is a group —NR^(c)R^(d) andR^(c) and R^(d) are both hydrogen atoms or one of them is a hydrogenatom and the remaining one of R^(c) or R^(d) is a straight or branchedalkyl or alkenyl group or it is an optionally substituted aryl orarylalkyl group; and R and R₂ are as above defined.

Another class of preferred compounds of the invention is represented bythe derivatives of formula (I) wherein R is either a group R^(a) withR^(a) as a hydrogen atom or a group —SO₂R^(a) with R^(a) as a straightor branched alkyl or optionally substituted aryl or arylalkyl group; andR₁ and R₂ are as above defined.

Another class of preferred compounds of the invention is represented bythe derivatives of formula (I) wherein R is a group —COR^(a) with R^(a)as a straight or branched alkyl, cycloalkyl or optionally substitutedaryl or arylalkyl group; and R₁ and R₂ are as above defined.

Another class of preferred compounds of the invention is represented bythe derivatives of formula (I) wherein R is a group —CONR^(a)R^(b) withone of R^(a) and R^(b) as a hydrogen atom and the other of R^(a) andR^(b) as a straight or branched alkyl, optionally substituted aryl orarylalkyl group; and R₁ and R₂ are as above defined.

Another class of preferred compounds of the invention is represented bythe derivatives of formula (I) wherein R is a group —CONR^(a)R^(b) andwherein R^(a) and R^(b) form, together with the nitrogen atom to whichthey are bonded, an optionally substituted 6 membered heterocyclic ring;and R₁ and R₂ are as above defined.

Another class of preferred compounds of the invention is represented bythe derivatives of formula (I) wherein R₂ is a straight or branchedalkyl or alkenyl group or it is a cycloalkyl, cycloalkyl-alkyl or anoptionally substituted aryl or arylalkyl group; and R and R₁ are asabove defined.

Preferably, within the above classes, R, R₁ and R₂ are selected, eachindependently, according to the meanings reported in tables I, II andIII of the experimental section.

For a reference to any specific compound of formula (I) of theinvention, optionally in the form of pharmaceutically acceptable salts,see the experimental section.

As set forth above, it is a further object of the present invention aprocess for preparing the compounds of formula (I).

Therefore, the compounds of formula (I) and the pharmaceuticallyacceptable salts thereof may be obtained by a process comprising:

a) reacting a formyl-succinonitrile alkaline salt derivative below

wherein Alk⁺ stands for Na⁺ or K⁺, with a suitable amine of formula (II)

R₂—NH₂  (II)

wherein R₂ is as above defined, under basic conditions, so as to obtainthe compound of formula (III)

b) reacting the compound of formula (III) with a base so as to obtain apyrrole derivative of formula (IV)

c) reacting the compound of formula (IV) with sodium nitromalonaldehydeso as to obtain the compound of formula (V)

d) reacting the compound of formula (V) under acidic conditions and inthe presence of a suitable alcohol of formula (VI)

R′—OH  (VI)

wherein R is a straight or branched lower alkyl group, so as to obtainthe compound of formula (VII)

e) reacting the compound of formula (VII) with tin(II) chloride so as toobtain a compound of formula (I)

wherein R₂ and R′ are as above defined and, optionally, reacting itaccording to any one of the alternative steps (f.1), (f.2), (f.3) or(f.4)

f.1) with any one of the compounds of formula (VIII), (IX), (X) or (XI)

R^(a)COZ  (VIII);

R^(a)NCO  (IX);

R^(a)SO₂Z  (X);

R^(a)OCOZ  (XI)

wherein R^(a) is as above defined and Z is a halogen atom, so as toobtain the compound of formula (I)

wherein R is as above defined and R is a group —COR^(a), —CONHR^(a),—SO₂R^(a) or —COOR^(a), respectively; or

f.2) with a suitable amine of formula (XII) in the presence oftriphosgene or of a suitable chloroformate

HNR^(a)R^(b)  (XII)

so as to obtain the above compound of formula (I) wherein R is a group—CONR^(a)R^(b); or

(f.3) with a suitable aldehyde or ketone derivative of formula (XIII)under reductive operative conditions

R^(a)—CO—R^(a)  (XIII)

wherein each R^(a) is the same or different as formerly defined, so asto obtain the above compound of formula (I) wherein R is a group—CH(R^(a))R^(a); or

(f.4) with an aromatic iodide or bromide of formula (XIV)

R^(a)—X  (XIV)

wherein X represents a iodine or bromine atom and R^(a) represents acarbocyclic or heterocyclic aryl group, in the presence of a suitablepalladium catalyst and of a ligand, so as to obtain a compound offormula (I) wherein R is R^(a) and this latter has the above reportedmeanings; and, optionally

g) converting the compound of formula (I) being obtained according toany one of steps (e), (f.1), (f.2), (f.3) or (f.4) into another compoundof formula (I) and/or into a pharmaceutically acceptable salt thereof.

The above process is an analogy process which can be carried outaccording to well-known methods.

According to step (a) of the process, the formyl-succinonitrile alkalinesalt is reacted with a suitable amine of formula (II) wherein R₂ is asdefined in formula (I), so as to get the corresponding compound offormula (III). Preferably, the reaction occurs by starting fromformyl-succinonitrile potassium salt.

The reaction is carried out under basic conditions, for instance in thepresence of sodium methylate, sodium ethylate, sodium hydride, potassiumtert-butoxide and the like, in a suitable solvent such as toluene ortetrahydrofuran, at a temperature ranging from room temperature toreflux. For a general reference to the operative conditions leading tothe preparation of the compound of formula (III) see, for instance,J.C.S. Perkin Trans. I: Organic and Bio-Organic Chemistry (1972-1999),(1975), (19), 1910-13; Synthetic Communication, 24(19), 2697-2705(1994); and Org. Proc. Res. Dev., 7 (2), 209-213, 2003.

According to step (b) of the process, the compound of formula (III) isfurther reacted under basic conditions without the need of beingisolated and further purified.

Preferably, the reaction is carried out with an alkali hydroxide, forinstance an excess of sodium or potassium hydroxide, in a suitablesolvent like a lower alcohol, for instance ethanol (for a generalreference to the above reaction conditions see, as an example, theaforementioned journals).

According to step (c) of the process, the compound of formula (IV) isreacted with sodium nitromalonaldehyde so as to get the formation of theazaindole bicyclic ring structure of formula (V). The reaction iscarried out in the presence of a suitable solvent, for instance a loweralcohol, under acidic conditions, for instance in the presence of amineral acid, preferably hydrochloric acid.

With the term lower alcohol herewith intended is any straight orbranched alcohol with from 1 to 4 carbon atom; preferably, the reactionis carried out in the presence of n-propanol.

According to step (d) of the process, the compound of formula (V) isconverted into the corresponding carboxyester derivative of formula(VII) by working according to conventional techniques, that is in thepresence of a suitable lower alcohol of formula (VI). Typically, byemploying a large excess of the same alcohol, it may act both as areactant as well as solvent medium. Preferably, the reaction is carriedout with n-propanol so as to lead to the compound of formula (VII)wherein R′ just represents n-propyl.

According to step (e) of the process, the nitro group of the compound offormula (VII) is reduced to the corresponding amino derivative. Thereduction is preferably carried out in the presence of tin(II) chloridein N-methylpyrrolidone (NMP) according to well-known methods. Clearly,any of the several methods known in the art to reduce nitro groups toamino groups, for instance comprising catalytic hydrogenation, may besuccessfully employed as well.

From the above, it is clear to the skilled man that the above reactionof step (e) allows to obtain a compound of formula (I) wherein R is ahydrogen atom, R₁ is a group —OR^(c) wherein R^(c) is just the alkylgroup R′ being introduced through step (d) of the process, e.g.n-propyl, and R₂ is as set forth in formula (I).

The compound of formula (I) thus obtained can then be converted into avariety of derivatives of formula (I) by working as described in any oneof steps from (f.1) to (f.4) of the process, according to well-knownmethods.

Typically, the compound of formula (I) of step (e) bearing an aminogroup in position 5 may be reacted: with a compound of formula (VIII) soas to get the corresponding carboxamido derivative wherein R is —COR^(a)and R^(a) is as above defined; with a compound of formula (IX) so as toget the corresponding ureido derivative wherein R is —CONHR^(a) andR^(a) is as above defined; with a compound of formula (X) so as to get asulfonamido derivative wherein R is —SO₂R^(a) and R^(a) is as abovedefined; with a compound of formula (XI) so as to get a carbamatederivative wherein R is —COOR^(a) and R^(a) is as above defined; with acompound of formula (XII) and triphosgene or a suitable chloroformate soas to get an ureido derivative wherein R is —CONR^(a)R^(b) and R^(a) andR^(b) are as above defined; with a compound of formula (XIII) underreductive operative conditions so as to get a derivative wherein R is—CH(R^(a))R^(a) and each R^(a), the same or different and independentlyfrom each other, is as above defined.

Any one of the above reactions is carried out according to conventionalmethods normally used in the preparation of functionalized aminoderivatives, by starting from the corresponding amine.

Within the compounds of formula (VIII), (X) or (XII) of step (f.1), Zrepresents a halogen atom and, even more preferably, a chlorine atom.

In this respect, the compound of formula (I) of step (e) is dissolved ina suitable solvent such as dichloromethane, dimethylformamide,tetrahydrofuran, dioxane or the like, and a suitable base such astriethylamine, diisopropylethylamine or sodium carbonate is addedtherein. The compound of general formula (VIII), (X) or (XI) is thenadded and the mixture stirred for a time of about 2 hours to about 15hours, at a temperature ranging from about 20° C. to about 80° C. Whenusing an isocyanate of general formula (IX), the reaction conditions arethe same as above reported except that the base may not be required. Inall of these reactions, a suitable catalyst such as dimethylaminopyridine may be optionally used.

According to step (f.2) of the process, the compound of formula (I)obtained in step (e) may be reacted with an amino derivative of formula(XII) in the presence of triphosgene or of a suitable chloroformate suchas, for instance, 4-nitrophenylchloroformate.

The reaction is carried out in a suitable solvent such as a halogenatedhydrocarbon, preferably dichloromethane, in the presence of a base suchas, for instance, diisopropylethylamine or triethylamine and by workingat room temperature.

According to step (f.3) of the process, the compound of formula (I) ofstep (e) is reacted, under reductive conditions, with an aldehyde orketone derivative of formula (XIII) so as to obtain the correspondingcompound of formula (I) wherein R is as above defined. From the above,it is clear to the skilled man that by employing an aldehyde derivativeof formula (XIII) wherein one of the two R^(a) is a hydrogen atom, thecorresponding derivative wherein R is —CH₂R^(a) may be obtained.Likewise, by employing a ketone derivative, compounds having R as—CH(R^(a))R^(a) may be obtained, wherein each R^(a) is, independentlyfrom each other, as set forth above but other than hydrogen.

According to step (f.4) of the process, the compound of formula (I) ofstep (e) is converted into the corresponding arylated derivative offormula (I) wherein R is R^(a) and R^(a) is an aryl group, hencecomprehensive of carbocyclic or heterocyclic aromatic groups.

The reaction is carried out according to known methods, with anysuitable aryl iodide or bromide of formula (XIV) in the presence of asuitable catalyst, for instance a palladium catalyst like palladiumacetate or Pd₂(dba)₃, and of a suitable ligand. See, for a generalreference to the above arylation reaction and operative conditionsthereof also inclusive of solvents, catalysts and ligands, J. Am. Chem.Soc., (2003), 125, 6653-55; JOC (2001), 66, 2560-2565; and JOC (2002),67, 6479-6486.

In addition to the above, it is also clear to the skilled person that,whenever desired, any of the above compounds of formula (I) thusprepared can be further converted into other derivatives of formula (I),as set forth in step (g), by working according to conventional methods.

As an example, the compounds of formula (I)

wherein R and R₂ are as set forth above and R′ represents a given alkylgroup, for instance n-propyl, may be converted into the compounds offormula (I):

h) wherein R and R₂ are as above defined and R₁ is —OR^(c) with R^(c)other than n-propyl, through transesterification reactions carried outaccording to well-known methods, for instance with a suitable compoundof formula (XV)

R^(c)—OH  (XV)

under acidic or basic conditions, optionally in the presence of suitablemetal based catalysts, like dibutyltin oxide or titanium alkoxides suchas, for instance, titanium(IV) ethoxide, titanium(IV) isopropoxide andthe like;

i) wherein R and R₂ are as above defined and R₁ is a group —OH, throughacidic or basic hydrolysis.

As an additional example, the compounds of formula (I) wherein R and R₂are as above defined and R₁ is a group —OR^(c) wherein R^(c) is an alkylgroup can be also converted into the corresponding amido derivatives offormula (I)

j) wherein R₁ is —NR^(c)R^(d), with R^(c) and R^(d) as above defined, bytreatment with ammonia or with a suitable amine of formula (XVI) or(XVII)

R^(c)—NH₂  (XVI);

R^(c)R^(d)NH  (XVII)

optionally in the presence of suitable catalysts such as, for instance,sodium cyanide or dimethylamino-pyridine.

Likewise, the compounds of formula (I) wherein R and R₂ are as abovedefined and R₁ is a group —OR^(c) with R^(c) as hydrogen can be alsoconverted into the corresponding amido derivatives of formula (I), byreaction with any suitable amine HNR^(c)R^(d), in the presence of asuitable condensing agent, for instance dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC),O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU) orbenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate(PyBOP).

In addition to the above, the compounds of formula (I) wherein R₂ is anaryl group (for instance phenyl, pyridyl, optionally substituted phenyl,and the like) or a hydrocarbon chain wherein the first carbon atomdirectly linked to the pyrrole nitrogen atom is a primary or secondarycarbon atom having formula —CH₂— (for instance benzyl, ethyl, n-propyland the like) or —CH< (for instance diphenylmethyl, isopropyl, and thelike), can be also prepared according to an alternative syntheticpathway.

The said pathway comprises, in particular, a different approach for thepreparation of the intermediate compound of formula (VII) of step (d).

Therefore, it is a further object of the invention a process forpreparing these latter compounds of formula (I) having R₂ as an arylgroup or a hydrocarbon chain wherein the first carbon atom directlylinked to the pyrrole nitrogen atom is a primary or secondary carbonatom, and the pharmaceutically acceptable salts thereof, which processcomprises:

k) reacting 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester with tetrabutylammonium nitrate (TBAN) in the presenceof trifluoroacetic anhydride (TFAA), so as to obtain a compound offormula (XVIII)

l) reacting the compound of formula (XVIII) under basic or acidichydrolysis conditions so as to obtain a compound of formula (XIX) or asalt thereof

m) reacting the compound of formula (XIX) with a carboxy protectingagent, for instance an esterifying agent, so as to obtain a compound offormula (XX)

wherein R stands for alkyl, for instance methyl;

n) reacting the compound of formula (XX) with a compound of formula(XXI)

R₂—Z′  (XXI)

wherein R₂ is an aryl group or a hydrocarbon chain having the firstcarbon atom directly linked to Z′ as a primary or secondary carbon atom,and Z′ is a halogen atom or any suitable leaving group such as tosyl ormesyl; so as to obtain a compound of formula (VII)

wherein R₂ and R are as above defined;

and then reacting the above compound of formula (VII) according to theremaining steps of the process from (e) to (g).

Also the above process is an analogy process which can be carried outaccording to well-known methods.

In particular, according to step (k) of the process, the nitration of1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methylester to yield the compound of formula (XVIII) is carried out withtetrabutylammonium nitrate (TBAN) in the presence of trifluoroaceticanhydride (TFAA). The reaction is carried out in a suitable solvent, forinstance a halogenated hydrocarbon such as dichloromethane, by workingat a temperature ranging from 0° C. to room temperature and for a timevarying from about 10 hours to about 30 hours.

According to step (I) of the process, the compound of formula (XVIII)can undergo hydrolysis under basic or acidic conditions. Preferably, thereaction is carried out in the presence of aqueous sodium hydroxide andof 2,2,2-trifluoroethanol (TFE), at a temperature ranging from roomtemperature to about 90° C. and for a time of from 4 hours to one day.According to the operative conditions being employed, the compound offormula (XVIII) could be obtained either in its acidic form or,alternatively, as a salt.

Preferably, the hydrolysis reaction is carried out under basicconditions, e.g. in the presence of sodium hydroxide, so as to obtainthe corresponding sodium salt.

According to step (m) of the process, the compound of formula (XIX) canbe esterified according to well-known operative conditions in thepresence of suitable alcohols. As an example, this reaction can beperformed in the presence of methanol so as to get the correspondingcarboxymethyl ester derivative of formula (XX) wherein R′ stands formethyl.

Alternatively, the compound of formula (XX) of step (m) wherein R′ juststands for methyl can be also prepared through the direct hydrolysis ofthe compound of formula (XVIII) according to known methods, for instancein the presence of potassium trimethylsylanolate in tetrahydrofuran(THF) or of triethylamine (TEA) in methanol.

Finally, according to step (n) of the process, the compound of formula(XX) is converted into the compound of formula (VII) through reactionwith a suitable compound of formula (XXI) wherein R₂ and Z′ have theabove reported meanings. The reaction can be performed in the presenceof a suitable base such as, for instance, potassium carbonate, sodiumhydride, potassium tertbutoxide, potassium hexamethyldisilazide (KHMDS),lithium hexamethyldisilazide (LHMDS), sodium hexamethyldisilazide(NHMDS), lithium diisopropylamide (LDA) ortert-butylimino(pyrrolidino)phosphorane (BTPP), in a suitable solventlike tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide,dimethylacetamide, and the like.

According to a preferred embodiment, the reaction is carried out withBTPP in dichloromethane.

Alternative methods are also known in the art to alkylate the pyrrolenitrogen atom of pyrrolo-pyridine cycles, for instance by starting fromactivated methylidene moieties (═CH₂) as reported in Perkin 1, (19),3317-3324, 2000; or Tetrahedron: Asymmetry, 11(23), 4719-4724, 2000.

From all of the above, it is clear to the skilled person that if acompound of formula (I), prepared according to the above processescomprehensive of any variant thereof, is obtained as an admixture ofisomers, their separation into the single isomers of formula (I),carried out according to conventional techniques, is still within thescope of the present invention.

Likewise, the conversion of a compound of formula (I) into apharmaceutically acceptable salt thereof or, alternatively, theconversion into the free compound (I) of a corresponding salt, accordingto well-known procedures in the art, is still within the scope of theinvention.

When preparing the compounds of formula (I) according to any variant ofthe process, which are all to be intended as within the scope of theinvention, optional functional groups within the starting materials, thereagents or the intermediates thereof, and which could give rise tounwanted side reactions, need to be properly protected according toconventional techniques.

Likewise, the conversion of these latter into the free deprotectedcompounds may be carried out according to known procedures.

The starting materials of the process object of the present invention,comprehensive of any possible variant, as well as any reactant thereof,are known compounds and if not commercially available per se may beprepared according to well-known methods.

As an example, the formyl-succinonitrile alkaline salt derivative can beprepared as described in the aforementioned cited references [see step(a)], by reacting commercially available butanedinitrile with ethylformate under basic conditions. Once obtained, the formyl-succinonitrilealkaline salt can be separated from the reaction mixture and thenreacted with the amine of formula (II) or, alternatively, directlyreacted with the amine of formula (II) in situ, without the need ofbeing isolated, as per step (a) of the process.

In addition, the compound1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methylester can be prepared as described in Tetrahedron Letters 40 (1999),5853-5854.

Likewise, the compounds of formula (II), (VI), from (VIII) to (XVII),and (XXI) are known or easily obtained according to known methods.

The intermediate compound of formula (XIX) of the process is novel and,hence, represents a further object of the invention.

In addition to the above, the compounds of formula (I) can beadvantageously prepared according to combinatorial chemistry techniqueswidely known in the art, by accomplishing the aforementioned reactionsbetween the intermediates in a serial manner and by working undersolid-phase-synthesis (SPS) conditions.

As an example, the intermediate carboxy ester derivatives of formula(VII) being obtained in steps (d) or (n) of the above processes, can befirst converted into the free carboxy acid derivatives by means ofhydrolysis carried out according to conventional methods, then easilysupported onto a polymeric resin, for instance through the formation ofa carboxamido group.

The intermediate thus supported may be subsequently reacted according tothe remaining steps of the process.

The above synthetic pathway can be summarised as follows:

Alternatively, the intermediate compound of formula (XIX) of step (I)can be first supported onto a polymeric resin and then reacted as perthe remaining steps of the process, for instance by inserting the R₂moiety in position 1 of the azaindole, by reducing the nitro group inposition 5 to amino, by functionalizing the amino group itself and bycleaving the resin so as to obtain the desired compounds of formula (I).

Any of the above reactions is carried out according to known methods, byworking as formerly reported, to obtain compounds of formula (I) whereinR₂ is an aryl group or a hydrocarbon chain having the first carbon atomattached to the pyrrole nitrogen atom as a primary or secondary carbonatom, as set forth above.

This latter synthetic pathway can be summarised as follows:

Preferably, the above resin is a commercially available polystyrenicresin including, for instance, Wang resin, Trityl resin, Cl-tritylresin, Rink amide resin, Tentagel OH resin and derivatives thereof.

According to a preferred embodiment of the invention, the polystyrenicresin is a derivatized formyl polystyrenic resin which may be obtainedby reacting a commercially available formyl polystyrenic resin, e.g.4-(4-formyl-3-methoxyphenoxy)butyryl AM resin, with a suitable aminoderivative under reductive conditions, for instance in the presence ofsodium borohydride and derivatives thereof, substantially as follows:

The reaction can be carried out in a suitable solvent such asdichloromethane and in the presence of acetic acid.

The polymer-supported-amino derivatives thus obtained, particularlythose, which are referable to as derivatized formyl polystyrenic resinabove, are widely known in the art.

In general, amines loaded onto formylpolystyrenic resins also known asAcid Sensitive MethoxyBenzaldehyde polystirene resins (AMEBA resin) areprepared by standard reductive amination in the presence of an excess ofamine in TMOF/DCE and NaBH(OAc)₃ or AcOH/DMF and NaCNBH₃, for instanceas reported in Tetrahedron Letters (1997), 38, 7151-7154; J. Am. Chem.Soc. (1998), 120, 5441; and Chem. Eur. J. (1999), 5, 2787.

Therefore, it is a further object of the present invention to providefor a process for preparing the compounds of formula (I), and thepharmaceutically acceptable salts thereof, which process comprises:

o) converting the compound of formula (VII) being prepared according tostep (d) or (n) of the aforementioned processes into the correspondingcarboxy acid derivative of formula (XXII)

wherein R₂ is as set forth in formula (I);

p) reacting the compound of formula (XXII) with a derivatized formylpolystyrenic resin of formula (XXIII)

(P)—CH₂—NHR^(c)  (XXIII)

wherein (P) is the resin and R^(c) is as set forth in formula (I), so asto obtain a compound of formula (XXIV)

q) reacting the compound of formula (XXIV) according to step (e) and,optionally, to any one of steps (f.1), (f.2), (f.3) or (f.4), so as toobtain a compound of formula (XXV)

wherein (P), R₂ and R^(c) are as set forth above and R is as defined informula (I);

r) cleaving the resin from the compound of formula (XXV) under acidicconditions so as to obtain a compound of formula (I) wherein R and R₂are as above defined and R₁ is a group —NHR^(c) wherein R^(c) is asabove defined; and, optionally,

s) converting the thus obtained compound of formula (I) into anothercompound of formula (I) and/or into a pharmaceutically acceptable saltsthereof.

According to step (o) of the process, the carboxy ester derivative offormula (VII) is hydrolized to the corresponding carboxy acid by workingaccording to known methods, for instance under acidic or basicconditions.

According to step (p) of the process, the reaction is performed in asuitable solvent, for instance NMP, in the presence ofdiisopropylethylamine (DIEA) dimethylaminopyridine (DMAP) and of asuitable condensing agent such as, for instance1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC),dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) orO-benzotriazolyl tetramethylisouronium tetrafluoroborate (TBTU).

According to step (q), the supported compound of formula (XXIV) is firstreduced as per step (e) of the process so as to obtain the aminoderivative, and optionally further reacted as formerly indicated, so asto give rise to a variety of compounds functionalised in position 5 ofthe pyrrolo[2,3-b]pyridine ring. The operative conditions areessentially those formerly reported by working under homogeneousoperative conditions.

Resin cleavage according to step (r) may be performed under acidicconditions in the presence of suitable acids such as, for instance,hydrochloric, trifluoroacetic, methanesulfonic or p-toluensulfonic acid.

Another object of the invention is also a process for preparing thecompounds of formula (I), and the pharmaceutically acceptable saltsthereof, which process comprises:

t) reacting the compound of formula (XIX) being obtained in previousstep (I) with a derivatized formyl polystyrenic resin of formula (XXIII)

(P)—CH₂—NHR^(c)  (XXIII)

wherein (P) is the resin and R^(c) is as set forth in formula (I), so asto obtain a compound of formula (XXVI)

u) reacting the compound of formula (XXVI) with a compound of formula(XXI) as described in step (n) so as to obtain a compound of formula(XXVII)

v) reducing the compound of formula (XXVII) to the corresponding aminoderivative of formula (XXVIII) as set forth in step (e)

and, optionally, converting it according to any one of steps (f.1),(f.2), (f.3) or (f.4), so as to obtain a compound of formula (XXV)

wherein (P), R₂ and R^(c) are as set forth above and R is as defined informula (I);

w) cleaving the resin from the compound of formula (XXV) according tostep (r) and, optionally, converting the thus obtained compoundaccording to step (s).

Clearly, by working according to combinatorial chemistry techniques asformerly indicated, a plurality of compounds of formula (I) can beobtained.

Hence, a further object of the present invention is to provide for alibrary of two or more compounds of formula (I)

wherein

R is selected from the group consisting of —R^(a), —COR^(a),—CONR^(a)R^(b), —SO₂R^(a) or —COOR^(a);

R₁ is a group —NR^(c)R^(d) or —OR^(c);

wherein R^(a), R^(b), R^(c) and R^(d), the same or different, are eachindependently hydrogen or a group optionally further substituted,selected from straight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, carbocyclic orheterocyclic aryl or aryl C₁-C₆ alkyl, heterocycle or heterocycle C₁-C₆alkyl or, taken together with the nitrogen atom to which they arebonded, either R^(a) and R^(b) as well as R^(c) and R^(d) may form anoptionally substituted 4 to 7 membered heterocycle, optionallycontaining one additional heteroatom or heteroatomic group selected fromS, O, N or NH;

R₂ is a group, optionally further substituted, selected from straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, C₃-C₆ cycloalkylor cycloalkyl C₁-C₆ alkyl, carbocyclic or heterocyclic aryl or arylC₁-C₆ alkyl, heterocycle or heterocycle C₁-C₆ alkyl; or isomers,tautomers, carriers, metabolites, prodrugs, and pharmaceuticallyacceptable salts thereof.

According to a preferred embodiment of the invention, the aforementionedlibrary comprises the compounds of formula (I) wherein R₁ is a group—NR^(c)R^(d) and R^(c) and R^(d) are both hydrogen atoms or one of themis a hydrogen atom and the remaining one of R^(c) or R^(d) is a straightor branched alkyl or alkenyl group or it is an optionally substitutedaryl or arylalkyl group; and R and R₂ are as above defined.

Also preferred is a library of compounds of formula (I) wherein R iseither a group R^(a) with R^(a) as a hydrogen atom or a group —SO₂R^(d)with R^(a) as a straight or branched alkyl group or optionallysubstituted aryl or arylalkyl group; and R₁ and R₂ are as above defined.

Also preferred is a library of compounds of formula (I) wherein R is agroup —COR^(a) with R^(a) as a straight or branched alkyl, cycloalkyl oroptionally substituted aryl or arylalkyl group; and R₁ and R₂ are asabove defined.

Also preferred is a library of compounds of formula (I) wherein R is agroup

—CONR^(a)R^(b) with one of R^(a) and R^(b) as a hydrogen atom and theother of R^(a) and R^(b) as a straight or branched alkyl, optionallysubstituted aryl or arylalkyl group; and R₁ and R₂ are as above defined.

Also preferred is a library of compounds of formula (I) wherein R is agroup

—CONR^(a)R^(b) and wherein R^(a) and R^(b) form, together with thenitrogen atom to which they are bonded, an optionally substituted 6membered heterocyclic ring; and R₁ and R₂ are as above defined.

Also preferred is a library of compounds of formula (I) wherein R₂ is astraight or branched alkyl or alkenyl group or it is a cycloalkyl,cycloalkyl-alkyl or an optionally substituted aryl or arylalkyl group;and R and R₁ are as above defined.

For a general reference to the above libraries of compounds of formula(I) see the experimental section.

From all of the above, it is clear to the skilled person that once alibrary of pyrrolo[2,3-b]pyridine derivatives is thus prepared, forinstance consisting of a few thousands of compounds of formula (I), thesaid library can be very advantageously used for screening towards givenkinases, as formerly reported.

See, for a general reference to libraries of compounds and uses thereofas tools for screening biological activities, J. Med. Chem. 1999, 42,2373-2382; and Bioorg. Med. Chem. Lett. 10 (2000), 223-226.

Pharmacology

The compounds of formula (I) are active as protein kinase inhibitors andare therefore useful, for instance, to restrict the unregulatedproliferation of tumour cells. In therapy, they are used in thetreatment of various tumours, such as those formerly reported, as wellas in the treatment of other cell proliferative disorders such aspsoriasis, vascular smooth cell proliferation associated withatherosclerosis and post-surgical stenosis and restenosis and in thetreatment of Alzheimer's disease.

The inhibiting activity of putative cdk/cyclin inhibitors and thepotency of selected compounds is determined through a method of assaybased on the use of the SPA technology (Amersham Pharmacia Biotech).

The assay consists of the transfer of radioactivity labelled phosphatemoiety by the kinase to a biotinylated substrate. The resulting³³P-labelled biotinylated product is allowed to bind tostreptavidin-coated SPA beads (biotin capacity 130 pmol/mg), and lightemitted was measured in a scintillation counter.

Inhibition Assay of CDK2/Cyclin a Activity

Kinase reaction: 4 μM in house biotinylated histone H1 (Sigma # H-5505)substrate, 10 μM ATP (0.1 microCi P³³γ-ATP), 1.1 nM Cyclin A/CDK2complex, inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH7.5, MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a96 U bottom. After incubation for 60 min at room temperature, thereaction was stopped by addition of 100 μl PBS buffer containing 32 mMEDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coatedSPA beads. After 20 min incubation, 110 μL of suspension were withdrawnand transferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl.After 4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

IC50 determination: inhibitors were tested at different concentrationsranging from 0.0015 to 10 μM. Experimental data were analyzed by thecomputer program GraphPad Prizm using the four parameter logisticequation:

y=bottom+(top−bottom)/(1+10̂((log IC50−x)*slope))

where x is the logarithm of the inhibitor concentration, y is theresponse; y starts at bottom and goes to top with a sigmoid shape.

Ki Calculation:

Experimental method: Reaction was carried out in buffer (10 mM Tris, pH7.5, 10 mM MgCl₂, 0.2 mg/ml BSA, 7.5 mM DTT) containing 3.7 nM enzyme,histone and ATP (constant ratio of cold/labeled ATP 1/3000). Reactionwas stopped with EDTA and the substrate captured on phosphomembrane(Multiscreen 96 well plates from Millipore). After extensive washing,the multiscreen plates were read on a top counter. Control (time zero)for each ATP and histone concentrations was measured.

Experimental design: Reaction velocities are measured at four ATP,substrate (histone) and inhibitor concentrations. An 80-pointconcentration matrix was designed around the respective ATP andsubstrate Km values, and the inhibitor IC50 values (0.3, 1, 3, 9 foldthe Km or IC50 values). A preliminary time course experiment in theabsence of inhibitor and at the different ATP and substrateconcentrations allows the selection of a single endpoint time (10 min)in the linear range of the reaction for the Ki determination experiment.

Kinetic parameter estimates: Kinetic parameters were estimated bysimultaneous nonlinear least-square regression using [Eq.1] (competitiveinhibitor respect to ATP, random mechanism) using the complete data set(80 points):

$\begin{matrix}{v = \frac{{Vm} \cdot A \cdot B}{\begin{matrix}{{\alpha \cdot {Ka} \cdot {Kb}} + {\alpha \cdot {Ka} \cdot B} + {a \cdot {Kb} \cdot A} +} \\{{A \cdot B} + {\alpha \cdot \frac{Ka}{Ki} \cdot I \cdot \left( {{Kb} + \frac{B}{\beta}} \right)}}\end{matrix}}} & \left\lbrack {{Eq}.\mspace{14mu} 1} \right\rbrack\end{matrix}$

where A=[ATP], B=[Substrate], I=[inhibitor], Vm=maximum velocity, Ka,Kb, Ki the dissociation constants of ATP, substrate and inhibitorrespectively. α and β the cooperativity factor between substrate and ATPbinding and substrate and inhibitor binding respectively.

In addition the selected compounds are characterized on a panel ofser/thre kinases strictly related to cell cycle (cdk2/cyclin E,cdk1/cyclin B1, cdk5/p25, cdk4/cyclin D1), and also for specificity onMAPK, PKA, EGFR, IGF1-R, Aurora-2 and Cdc7.

Inhibition Assay of cdk2/Cyclin E Activity

Kinase reaction: 10 μM in house biotinylated histone H1 (Sigma # H-5505)substrate, 30 μM ATP (0.3 microCi P³³γ-ATP), 4 ng GST-Cyclin E/CDK2complex, inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH7.5, MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a96 U bottom. After incubation for 60 min at room temperature, thereaction was stopped by addition of 100 μl PBS buffer containing 32 mMEDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coatedSPA beads. After 20 min incubation, 110 μL of suspension were withdrawnand transferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl.After 4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

IC50 determination: see above

Inhibition Assay of CDK1/Cyclin B1 Activity

Kinase reaction: 4 μM in house biotinylated histone H1 (Sigma # H-5505)substrate, 20 μM ATP (0.2 microCi P³³γ-ATP), 3 ng Cyclin B/CDK1 complex,inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5,MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 Ubottom. After 20 min at r.t. incubation, reaction was stopped by 100 μlPBS+32 mM EDTA+0.1% Triton X-100+500 μM ATP, containing 1 mg SPA beads.Then a volume of 110 μl is transferred to Optiplate.

After 20 min. incubation for substrate capture, 100 μl 5M CsCl wereadded to allow stratification of beads to the top of the Optiplate andlet stand 4 hours before radioactivity counting in the Top-Countinstrument.

IC50 determination: see above

Inhibition Assay of CDK5/P25 Activity

The inhibition assay of cdk5/p25 activity is performed according to thefollowing protocol.

Kinase reaction: 10 μM biotinylated histone H1 (Sigma # H-5505)substrate, 30 μM ATP (0.3 microCi P³³γ-ATP), 15 ng CDK5/p25 complex,inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5,MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 Ubottom. After incubation for 35 min at room temperature, the reactionwas stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPAbeads. After 20 min incubation, 110 μL of suspension were withdrawn andtransferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

IC50 determination: see above

Inhibition Assay of CDK4/Cyclin D1 Activity

Kinase reaction: 0.4 uM μM mouse GST-Rb (769-921) (# sc-4112 from SantaCruz) substrate, 10 μM ATP (0.5 μCi P³³γ-ATP), 100 ng of baculovirusexpressed GST-cdk4/GST-Cyclin D1, suitable concentrations of inhibitorin a final volume of 50 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl₂ 10 mM,7.5 mM DTT+0.2 mg/ml BSA) were added to each well of a 96 U bottom wellplate. After 40 min at 37° C. incubation, reaction was stopped by 20 μlEDTA 120 mM.

Capture: 60 μl were transferred from each well to MultiScreen plate, toallow substrate binding to phosphocellulose filter. Plates were thenwashed 3 times with 150 μl/well PBS Ca⁺⁺/Mg⁺⁺ free and filtered byMultiScreen filtration system.

Detection: filters were allowed to dry at 37° C., then 100 μl/wellscintillant were added and ³³P labeled Rb fragment was detected byradioactivity counting in the Top-Count instrument.

IC50 determination: see above

Inhibition Assay of MAPK Activity

Kinase reaction: 10 μM in house biotinylated MBP (Sigma # M-1891)substrate, 15 μM ATP (0.15 microCi P³³γ-ATP), 30 ng GST-MAPK (UpstateBiotechnology #14-173), inhibitor in a final volume of 30 μl buffer(TRIS HCl 10 mM pH 7.5, MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) wereadded to each well of a 96 U bottom. After incubation for 35 min at roomtemperature, the reaction was stopped by addition of 100 μl PBS buffercontaining 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/mlstreptavidin coated SPA beads. After 20 min incubation, 110 μL ofsuspension were withdrawn and transferred into 96-well OPTIPLATEscontaining 100 μl of 5M CsCl. After 4 hours, the plates were read for 2min in a Packard TOP-Count radioactivity reader.

IC50 determination: see above

Inhibition Assay of PKA Activity

Kinase reaction: 10 μM in house biotinylated histone H1 (Sigma # H-5505)substrate, 10 μM ATP (0.2 microM P³³γ-ATP), 0.45 U PKA (Sigma #2645),inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5,MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 Ubottom. After incubation for 90 min at room temperature, the reactionwas stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPAbeads. After 20 min incubation, 110 μL of suspension were withdrawn andtransferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

IC50 determination: see above

Inhibition Assay of EGFR Activity

Kinase reaction: 10 μM in house biotinylated MBP (Sigma # M-1891)substrate, 2 μM ATP (0.04 microCi P³³γ-ATP), 36 ng insect cell expressedGST-EGFR, inhibitor in a final volume of 30 μl buffer (Hepes 50 mM pH7.5, MgCl₂ 3 mM, MnCl₂ 3 mM, DTT 1 mM, NaVO₃ 3 μM, +0.2 mg/ml BSA) wereadded to each well of a 96 U bottom. After incubation for 20 min at roomtemperature, the reaction was stopped by addition of 100 μl PBS buffercontaining 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/mlstreptavidin coated SPA beads. After 20 min incubation, 110 μL ofsuspension were withdrawn and transferred into 96-well OPTIPLATEscontaining 100 μl of 5M CsCl. After 4 hours, the plates were read for 2min in a Packard TOP-Count radioactivity reader.

IC₅₀ determination: see above

Inhibition Assay of IGF1-R Activity

The inhibition assay of IGF1-R activity is performed according to thefollowing protocol.

Enzyme activation: IGF1-R must be activated by auto-phosphorylationbefore starting the experiment. Just prior to the assay, a concentratedenzyme solution (694 nM) is incubated for half a hour at 28° C. in thepresence of 100 μM ATP and then brought to the working dilution in theindicated buffer.

Kinase reaction: 10 μM biotinylated IRS1 peptide (PRIMM) substrate, 0-20μM inhibitor, 6 μM ATP, 1 microCi ³³P-ATP, and 6 nM GST-IGF1-R(pre-incubated for 30 min at room temperature with cold 60 μM cold ATP)in a final volume of 30 μl buffer (50 mM HEPES pH 7.9, 3 mM MnCl₂, 1 mMDTT, 3 μM NaVO₃) were added to each well of a 96 U bottom well plate.After incubation for 35 min at room temperature, the reaction wasstopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500 μMcold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads.After 20 min incubation, 110 μL of suspension were withdrawn andtransferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

Inhibition Assay of Aurora-2 Activity

Kinase reaction: 8 μM biotinylated peptide (4 repeats of LRRWSLG), 10 μMATP (0.5 uCi P³³γ-ATP), 7.5 ng Aurora 2, inhibitor in a final volume of30 μl buffer (HEPES 50 mM pH 7.0, MgCl₂ 10 mM, 1 mM DTT, 0.2 mg/ml BSA,3 μM orthovanadate) were added to each well of a 96 U bottom well plate.After 60 minutes at room temperature incubation, reaction was stoppedand biotinylated peptide captured by adding 100 μl of bead suspension.

Stratification: 100 μl of CsCl2 5 M were added to each well and letstand 4 hour before radioactivity was counted in the Top-Countinstrument.

IC50 determination: see above

Inhibition Assay of Cdc7/dbf4 Activity

The inhibition assay of Cdc7/dbf4 activity is performed according to thefollowing protocol.

The Biotin-MCM2 substrate is trans-phosphorylated by the Cdc7/Dbf4complex in the presence of ATP traced with γ³³-ATP. The phosphorylatedBiotin-MCM2 substrate is then captured by Streptavidin-coated SPA beadsand the extent of phosphorylation evaluated by β counting.

The inhibition assay of Cdc7/dbf4 activity was performed in 96 wellsplate according to the following protocol.

To each well of the plate were added:

-   -   10 μl substrate (biotinylated MCM2, 6 μM final concentration)    -   10 μl enzyme (Cdc7/Dbf4, 17.9 nM final concentration)    -   10 μl test compound (12 increasing concentrations in the nM to        μM range to generate a dose-response curve)    -   10 μl of a mixture of cold ATP (2 μM final concentration) and        radioactive ATP (1/5000 molar ratio with cold ATP) was then used        to start the reaction which was allowed to take place at 37° C.

Substrate, enzyme and ATP were diluted in 50 mM HEPES pH 7.9 containing15 mM MgCl₂, 2 mM DTT, 3 μM NaVO₃, 2 mM glycerophosphate and 0.2 mg/mlBSA. The solvent for test compounds also contained 10% DMSO.

After incubation for 60 minutes, the reaction was stopped by adding toeach well 100 μl of PBS pH 7.4 containing 50 mM EDTA, 1 mM cold ATP,0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads.

After 20 min incubation, 110 μL of suspension were withdrawn andtransferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

IC50 determination: see above.

The compounds of formula (I) of the present invention, suitable foradministration to a mammal, e.g. to humans, are administered by theusual routes and the dosage level depends upon the age, weight,conditions of the patient and the administration route.

For example, a suitable dosage adopted for oral administration of acompound of formula (I) preferably ranges from about 10 to about 500 mgper dose, from 1 to 5 times daily.

The compounds of the invention can be administered in a variety ofdosage forms, e.g. orally, in the form of tablets, capsules, sugar orfilm coated tablets, liquid solutions or suspensions; rectally in theform of suppositories; parenterally, e.g. intramuscularly, or byintravenous and/or intrathecal and/or intraspinal injection or infusion.

In addition, the compounds of the invention can be administered eitheras single agents or, alternatively, in combination with known anticancertreatments such as radiation therapy or chemotherapy regimen incombination with cytostatic or cytotoxic agents, antibiotic-type agents,alkylating agents, antimetabolite agents, hormonal agents, immunologicalagents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2inhibitors), metallomatrixprotease inhibitors, telomerase inhibitors,tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HERagents, anti-EGFR agents, anti-angiogenesis agents, farnesyl transferaseinhibitors, ras-raf signal transduction pathway inhibitors, cell cycleinhibitors, other cdks inhibitors, tubulin binding agents, topoisomeraseI inhibitors, topoisomerase II inhibitors and the like, optionallywithin liposomal formulations thereof.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described above andthe other pharmaceutically active agent within the approved dosagerange.

Compounds of formula (I) can also be used sequentially with knownanticancer agents when a combination formulation is inappropriate.

The present invention also includes pharmaceutical compositionscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptable excipient(which can be a carrier or a diluent).

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a pharmaceutically suitable form.

For example, the solid oral forms can contain, together with the activecompound, diluents, e.g. lactose, dextrose, saccharose, sucrose,cellulose, corn starch or potato starch; lubricants, e.g. silica, talc,stearic, magnesium or calcium stearate, and/or polyethylene glycols;binding agents, e.g. starches, arabic gum, gelatin, methylcellulose,carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents,e.g. a starch, alginic, alginates or sodium starch glycolate;effervescing mixtures; dyestuffs; sweeteners; wetting agents such aslecithin, polysorbates, laurylsulfates; and, in general, non-toxic andpharmacologically inactive substances used in pharmaceuticalformulations. Said pharmaceutical preparations may be manufactured inknown manner, for example, by means of mixing, granulating, tabletting,sugar-coating, or film-coating processes.

The liquid dispersions for oral administration can also be e.g. syrups,emulsions and suspensions.

The syrups can contain as carrier, for example, saccharose or saccharosewith glycerin and/or mannitol and/or sorbitol.

The suspensions and the emulsions can contain as carrier, for example, anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol.

The suspension or solutions for intramuscular injections can contain,together with the active compound, a pharmaceutically acceptablecarrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g.propylene glycol, and, if desired, a suitable amount of lidocainehydrochloride. The solutions for intravenous injections or infusions maycontain as carrier, for example, sterile water or preferably they may bein the form of sterile, aqueous, isotonic saline solutions or they maycontain as a carrier propylene glycol.

The suppositories can contain together with the active compound apharmaceutically acceptable carrier, e.g. cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty ester surfactant or lecithin.

The following examples are herewith intended to better illustrate thepresent invention without posing any limitation to it.

Experimental Section General Methods

Flash Chromatography was performed on silica gel (Merck grade 9395,60A). The high pressure liquid chromatography retention times (HPLC:r.t. values) were determined by:

Method 1 (HPLC_(—)1):

Instrumentation: Hewlett Packard 1312A binary pump; Gilson 215autosampler fitted with a 1 ml syringe, Polymer Labs PL1000 EvaporativeLight Scattering Detector (ELSD), and a Micromass ZMD mass spectrometeroperating in Electrospray positive ionisation mode. The LC eluent issplit and approximately 200 μl/min enters the mass spectrometer, 800μl/min to the ELS.

Chromatographic condition: HPLC mobile phases consisting of 0.1%trifluoroacetic acid in HPLC grade water (A) and 0.1% trifluoroaceticacid in HPLC grade acetonitrile (B). The HPLC gradient is shown in thetable below

Time (mins) % A % B 0.0 100 0 1.8 5 95 2.1 5 95 2.3 100 0 2.4 100 0 Runtime: 2.4 minutes Flow rate: 1 ml/min Injection vol: 3 μl Columntemperature: ambient (20° C.) Column: 50 × 2.0 mm Hypersil C18 BDS; 5 μmELS Detector: Nebuliser Temperature 80° C. Evaporation temperature 90°C. Gas Flow 1.5 l/hr MS Detector: m/z 150-800 @ 0.5 secs/scan, 0.1second interscan delay Cone voltage 25 V, Source Temp. 140° C. DryingGas 350 l/hrELSD retention times (HPLC r.t.) are given in minutes. Mass are given asm/z ratio.

Method 2 (HPLC_(—)2):

Instrumentation: Waters 2790 HPLC system equipped with a 996 Waters PDAdetector and Micromass mod. ZQ single quadrupole mass spectrometer,equipped with an electrospray (ESI) ion source.

Chromatographic condition: RP18 Waters X Terra (4.6×50 mm, 3.5 μm)column; Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 withacetic acid/acetonitrile 95:5), and Mobile phase B was H₂O/acetonitrile(5:95). Gradient from 10 to 90% B in 8 minutes, hold 90% B 2 minutes. UVdetection at 220 nm and 254 nm. Flow rate 1 ml/min. Injection volume 10μl. Full scan, mass range from 100 to 800 amu. Capillary voltage was 2.5KV; source temp. was 120° C.; cone was 10 V. Retention times (HPLC r.t.)are given in minutes at 220 nm or at 254 nm. Mass are given as m/zratio.

When necessary, the compounds have been purified by preparative HPLC ona Waters Symmetry C18 (19×50 mm, 5 μm) column using a waters preparativeHPLC 600 equipped with a 996 Waters PDA detector and a Micromass mod. ZQsingle quadrupole mass spectrometer, electron spray ionization, positivemode. Mobile phase A was water 0.01% TFA, and Mobile phase B wasacetonitrile. Gradient from 10 to 90% B in 8 min, hold 90% B 2 min. Flowrate 20 ml/min.

¹H-NMR spectrometry was performed on a Bruker AVANCE 400 MHz single bayinstrument with gradients. It is equipped with a QNP probe(interchangeable 4 nuclei probe—¹H, 13C, 19F and 31P) (NMR method 1) oron a Mercury VX 400 operating at 400.45 MHz equipped with a 5 mm doubleresonance probe [1H (15N-31P) ID_PFG Varian] (NMR method 2).

As formerly indicated, several compounds of formula (I) of the inventionhave been synthesized in parallel, according to combinatorial chemistrytechniques.

In this respect, some compounds thus prepared have been conveniently andunambiguously identified, as per the coding system of tables from IV toIX, together with HPLC retention time (methods 1 and 2) and mass.

Each code, which identifies a single specific compound of formula (I),consists of four units A-M-B-C.

A represents any substituent R₁—[see formula (I)] and is attached to therest of the azaindole moiety through the carbon atom of the carbonylgroup so as to get azaindole derivatives being substituted in position3; each A radical (substituent) is represented in the following table I.

B represents any substituent R—[see formula (I)] and is attached to therest of the azaindole moiety through the nitrogen atom of the NH groupso as to get azaindole derivatives being substituted in position 5; eachB radical (substituent) is represented in the following table II.

C represents any substituent R₂—[see formula (I)] and is attached to therest of the azaindole moiety through the indolic nitrogen atom so as toget azaindole derivatives being substituted in position 1; each Cradical (substituent) is represented in the following table III.

M refers to the central core of the trivalent azaindole moiety beingsubstituted in position 1 by groups C, in position 3 (through thecarbonyl group) by groups A, and in position 5 (through the NH group) bygroups B, substantially as follows:

For ease of reference, each A, B or C groups of tables I, II and III hasbeen identified with the proper chemical formula also indicating thepoint of attachment with the rest of the molecule M.

Just as an example, the compound A3-M-B5-C2 of table IV (entry 1)represents an azaindole M being substituted in position 5 by the groupB5 (through the NH group), in position 3 by the group A3 (through the COgroup) and in position 1 by the group C2; likewise, the compoundA9-M-B9-C2 of table IX (entry 40) represents an azaindole M beingsubstituted in position 5 by the group B9 (through the NH group), inposition 3 by the group A9 (through the CO group) and in position 1 bythe group C2, as follows:

TABLE I A groups Fragment Code

A1

A2

A3

A4

A5

A6

A7

A8

A9

TABLE II B groups Fragment Code

B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12 H B13

B14

B15

TABLE III C groups Fragment Code

C1

C2

C3

C4

C5

C6

C7

C8

C9

Example 1 Preparation of1-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

To a solution of 5.85 g (35.8 mmol) of5-amino-1-tert-butyl-1H-pyrrole-3-carbonitrile, being prepared asdisclosed in Org. Proc. Res. Dev., 7(2), 209-213, 2003, in 120 mL ofn-propanol, it was added sodium nitromalonaldehyde (6.02 g, 43.0 mmol)portionwise under stirring at room temperature. The resulting mixturewas treated dropwise with 37% hydrochloric acid (4.6 mL, 55.2 mmol) andheated at 100° C. for 2 hours. The reaction mass was concentrated undervacuum to ⅓ of the initial volume and kept at 4° C. for 18 hours. Theprecipitate was filtered off, washed thoroughly with 15% aqueous ethanol(35 mL), water (5 mL) and finally dried to afford 7.14 g of the titlecompound as a light brown solid.

m.p.=216-218° C.

Yield=81.5%

¹H-NMR (DMSO): 1.77 (s, 9H), 8.81 (s, 1H), 8.90 (d, 1H, J=2.63 Hz), 9.26(d, 1H, J=2.63 Hz).

Example 2 Preparation of1-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid propylester

To a suspension of 5.0 g (20.47 mmol) of1-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile in 125 mLof n-propanol, 7.78 g of p-toluensulfonic acid were added understirring. The mixture was heated at reflux for 40 hours and then it wascooled to room temperature and diluted with 70 mL of tert-butyl methylether. The precipitate was filtered off and the clear filtrate wasconcentrated under vacuum to a small volume (about 40-50 mL). Thesuspension was cooled to −5/0° C. and kept at this temperature for 2hours. The solid was filtered, washed with 20 mL of 1:1 mixture ofn-propanol and tert-butyl methyl ether and dried to afford 5.50 g of thetitle compound as a cream-colored solid.

m.p. 116-120° C.

Yield=88%

¹H-NMR (DMSO): 1.00 (t, 3H), 1.70-1.80 (m, 2H), 1.80 (s, 9H), 4.27 (t,2H), 8.42 (s, 1H), 9.01 (d, 1H, J=2.63 Hz), 9.22 (d, 1H, J=2.63 Hz).

Example 3 Preparation of1-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

To a suspension of 5.00 g (16.38 mmol) of1-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid propylester in 50 mL of 95° ethanol, it was added 2M NaOH (50 mL; 100 mmol)under stirring. The mixture was heated to reflux for 1 hour obtainingthe complete consumption of the substrate. The resulting solution wascooled to room temperature and concentrated under reduced pressure to aslurry that was diluted with 250 mL of water and washed with 100 mL of a1:1 mixture of diethyl ether and ethyl acetate. The aqueous layer wastreated with 5M HCl (37 mL; 185 mmol) under efficient stirring at roomtemperature. The precipitate was filtered off, washed twice with 10 mLof water and dried so as to afford 3.84 g of the title compound as awhite solid.

m.p.=278-281° C. dec.

Yield=89%

¹H-NMR (DMSO): 1.79 (s, 9H), 8.36 (s, 1H), 9.03 (d, 1H, J=2.63 Hz), 9.20(d, 1H, J=2.63 Hz), 12.77 (bs, 1H).

Example 4 Preparation of methyl5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

To an ice-cooled solution of 187.7 g (0.616 mol) of tetrabutylammoniumnitrate in 2.07 L of dichloromethane, trifluoroacetic anhydride (85.7mL, 0.616 mol) was added dropwise over a period of 25 minutes, undernitrogen. This mixture was slowly transferred, via cannula, to apreformed solution of 150.0 g (0.474 mol) of1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methylester in 2.7 L of dichloromethane at +4° C. The reaction mixture wasstirred at +4° C. for 4 hours and then kept at this temperature foradditional 23 hours. The cold reaction mass was poured in 2.3 L of waterand stirred for 1 hour. The aqueous layer was separated and extractedagain with 1 L of dichloromethane. The combined organic extracts wereconcentrated under vacuum to a thick yellow suspension, which wastreated with 1.05 L of methanol. The slurry was cooled at 0° C. andstirred for further 1 hour before it was filtered, washed with methanoland dried to afford 128 g of pure title compound as a woolly yellowsolid (Yield=74.7%). m.p.=195-196° C. ¹H-NMR (DMSO): 3.91 (s, 3H),7.64-7.69 (m, 2H), 7.76-7.81 (m, 1H), 8.25-8.27 (m, 2H), 8.74 (s, 1H),8.96 (d, 1H, J=2.58 Hz), 9.27 (d, 1H, J=2.58 Hz).

Example 5 Preparation of disodium5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

To a suspension of 95.7 g (0.265 mol) of the compound of example 4 in1.34 L of 2,2,2-trifluoroethanol, 0.545 L of 17% NaOH were added over aperiod of 40 minutes under vigorous stirring. The yellow-orange mixturewas heated at reflux for 16 hours and then it was cooled to 0° C. andstirred for 2 additional hours. The precipitate was filtered off, washedwith acetone and dried to afford 79.8 g of the title compound as anorange crystalline solid

(Yield=93.1% as tetrahydrate). m.p. >230° C.

¹H-NMR (DMSO): 7.83 (bs, 1H), 8.89 (d, 1H, J=2.80 Hz), 9.07 (bs, 1H).

Example 6 Preparation of 5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

To a clear solution of the compound of example 5 (88.10 g, 0.35 mol) in2.65 L of water, it was added dropwise concentrated HCl (52.6 mL, 0.526mol) diluted with 105 mL of water over a period of 50 minutes underefficient stirring at ambient temperature. The resulting suspension wascooled at +4° C. and stirred for further 1 hour. The precipitate wasfiltered off, washed with water and finally dried to give 55.6 g of thetitle compound as a light-yellow powder (Yield=98.5% (title 95%)).

m.p.=282-285° C. dec.

¹H-NMR (DMSO): 8.41 (d, 1H, J=2.83 Hz), 9.00 (d, 1H, J=2.59 Hz), 9.16(d, 1H, J=2.59 Hz), 12.5-13.0 (bs, 1H), 13.14 (s, 1H).

Example 7 General Procedure: Loading of 4-Fluorobenzylamine(Corresponding to Fragment A3 of Table I) onto Acid Sensitive MethoxyBenzaldehyde Polystyrene Resin (AMEBA II Resin)

4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin [copoly(styrene-1% dvb)100-200 mesh] (1.5 g, 1 eq, loading 0.94 mmol/g) was swollen in DCM andthen filtered. A mixture of THF/DCM (4:1, 15 ml), 4-fluorobenzylamine (6eq.) and AcOH (6 eq.) was added. After 15 minutes, NaBH(OAc)₃ was addedand the reaction was shaken over night at room temperature. Afterfiltration, the resin was washed with methanol (×3), DMF/DCM (1:1) (×3)and DCM (×5).

Example 8 Step 8.1: Loading of the Azaindole Scaffold onto the Resin ofExample 7

To the resin (1.5 g, 0.77 mmol/g, 1.16 mmol) of example 7 in anhydrousDMF (15 ml), it was added 5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid (0.359 g, 1.73 mmol), TBTU (0.556 g, 1.73 mmol) and DIPEA (0.44 g,3.48 mmol). The reaction mixture was shaken at room temperature for 20hours and then the resin was isolated by filtration. The resin waswashed sequentially with DMF (25 ml), DCM (25 ml), DMF (25 ml), DCM (25ml), MeOH (25 ml), DCM (25 ml), MeOH (25 ml), DCM (25 ml), MeOH (25 ml),TBME (25 ml×2) and dried in vacuo to give the resin bound 7-azaindole(1.70 g).

Resin Loading Check

Resin loading check was carried out to demonstrate the complete loadingof the building block onto the resin and that no oligomerization hasoccurred whilst coupling with TBTU. Benzoyl chloride was used in orderto cap unreacted resin loaded amine (i.e. 4-fluorobenzylamine, forexample 8) and to acylate the 1-NH azaindole. The absence of benzamide(i.e. N-(4-fluorobenzyl)benzamide, for example 8) in the cleaved mixturedemonstrates the quantitative loading of the scaffold onto the resin.The presence of 1-N-benzoylazaindole or of 1-NH-azaindole, demonstratethat no homocoupling of the 3-carboxy-5-nitro-7-azaindole has occurredduring the resin loading step. To the resin obtained following theprocedure described in example 8 (step 8.1) (0.035 g, 0.027 mmol) in DCM(1 ml) it was added DIPEA (0.035 g, 0.265 mmol) and benzoyl chloride(0.038 g, 0.265 mmol). The reaction mixture was shaken for 4 hours andthe resin isolated by filtration. The resin was washed sequentially withDMF (1 ml), DCM (1 ml), DMF (1 ml), DCM (1 ml), MeOH (1 ml), water (1ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), TBME(1 ml×2) and then air dried. The product was cleaved from the resin (1ml of 60% TFA/DCM for 20 minutes) to give an off white solid (0.007 g,64%).

LCMS (HPLC_(—)1) (N-benzoylated indole): m/z 419 [M+H]⁺ @ r.t. 1.56 min(97% by ELS detection).

Step 8.2: N-Alkylation of the Resin Bound 7-Azaindole

To the resin (0.85 g, corresponding to 0.58 mmol) of step (8.1) inanhydrous DCM (20 ml) it was added BTPP (0.540 g, 1.74 mmol) andiodomethane (R₂ corresponding to fragment C2 of table III, 0.821 g, 5.8mmol). The reaction mixture was shaken at room temperature for 20 hoursand then the resin was isolated by filtration. The resin was washedsequentially with DMF (25 ml), DCM (25 ml), DMF (25 ml), DCM (25 ml),MeOH (25 ml), DCM (25 ml), MeOH (25 ml), DCM (25 ml), MeOH (25 ml), TBME(25 ml×2) and dried in vacuo to give the resin boundN-methylated-7-azaindole (0.85 g). 0.01 g of the resin were cleaved (1ml of 60% TFA/DCM for 20 minutes) to give an off-white solid (0.0015 g,60%).

LCMS: m/z 329 [M+H]⁺ @ r.t. 1.72 min (94% @ 215 nm).

Step 8.3: Reduction of the Nitro Group

To the resin of step (8.2) (0.85 g) in NMP (10 ml), it was added tin(II)chloride dihydrate (1.3 g, 5.8 mmol). The reaction mixture was shaken atroom temperature for 20 hours and then the resin was isolated byfiltration. The resin was washed sequentially with DMF (10 ml), DCM (10ml), DMF (10 ml), DCM (10 ml), MeOH (10 ml), water (10 ml), MeOH (10ml), DCM (10 ml), MeOH (10 ml), DCM (10 ml), MeOH (10 ml), TBME (10ml×2) and dried in vacuo to give the corresponding resin boundN-methylated-5-amino-7-azaindole (0.825 g). 0.01 g of the resin werecleaved (1 ml of 60% TFA/DCM for 20 minutes) to give an off-white solid(0.0015 g, 65%).

LCMS (HPLC_(—)1): m/z 299 [M+H]⁺ @ r.t. 0.97 min (100% by ELSdetection).

The above resin bound azaindole was further reacted according to thealternative steps below so as to get carboxamido, sulfonamido and ureidoderivatives.

Preparation of A3-M-B5-C2 Step 8.4: Capping with Acid ChlorideDerivatives

To the resin of step (8.3) (0.11 g, corresponding to 0.077 mmol) in DCM(1 ml) it was added Hunig's base (0.050 g, 0.385 mmol) followed bybenzoyl chloride (group —COR^(a) corresponding to fragment B5 of tableII, 0.054 g, 0.385 mmol). The reaction mixture was shaken at roomtemperature for 20 hours and then the resin was isolated by filtration.The resin was washed sequentially with DMF (1 ml), DCM (1 ml), DMF (1ml), DCM (1 ml), MeOH (1 ml), water (1 ml), MeOH (1 ml), DCM (1 ml),MeOH (1 ml), DCM (1 ml), MeOH (1 ml), TBME (1 ml×2) and then air dried.The resin was shaken in acetonitrile/ammonia solution (1 ml, 4:1) for 4hours and then isolated by filtration. The resin was washed sequentiallywith DMF (1 ml), DCM (1 ml), DMF (1 ml), DCM (1 ml), MeOH (1 ml), water(1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml),TBME (1 ml×2) and then air dried. The product was cleaved from the resin[60% TFA/DCM, 3×(3×0.5 ml)] to give an off white solid (0.026 g, 84%)corresponding to compound A3-M-B5-C2 (see entry 1 of table IV below).LCMS (HPLC_(—)1): m/z 403 [M+H]⁺ @ r.t. 1.29 min (100% by ELSdetection).

Following the procedure described in example 8 and by using any properreactant as per the process of the invention that is, by supporting anysuitable amine onto the resin, by functionalizing position 1 of theazaindole moiety with any suitable reactant, by acylating the aminofunction in position 5 of the azaindole moiety with any suitable acylchloride derivative and by finally carrying out resin cleavage, thefollowing compounds of table IV were also prepared.

TABLE IV HPLC r.t. Entry Compound method (min) [M + H]⁺ 1 A3-M-B5-C2HPLC_1 1.29 403 2 A3-M-B6-C2 HPLC_1 1.04 341 3 A4-M-B5-C2 HPLC_1 1.1 3374 A4-M-B6-C2 HPLC_1 0.85 275 5 A7-M-B5-C2 HPLC_1 1.26 415 6 A7-M-B6-C2HPLC_1 1.02 353 7 A6-M-B5-C2 HPLC_1 1.11 337 8 A6-M-B6-C2 HPLC_1 0.85275 9 A1-M-B5-C2 HPLC_1 1.26 385 10 A1-M-B6-C2 HPLC_1 1.01 323 11A5-M-B5-C2 HPLC_1 1.32 399 12 A5-M-B6-C2 HPLC_1 1.1 337 13 A8-M-B5-C2HPLC_1 1.07 367 14 A8-M-B6-C2 HPLC_1 0.83 305 15 A2-M-B5-C2 HPLC_1 1.09335 16 A2-M-B6-C2 HPLC_1 0.82 273 17 A3-M-B5-C5 HPLC_1 1.5 479 18A3-M-B6-C5 HPLC_1 1.3 417 19 A4-M-B5-C5 HPLC_1 1.38 413 20 A4-M-B6-C5HPLC_1 1.15 351 21 A7-M-B5-C5 HPLC_1 1.48 491 22 A7-M-B6-C5 HPLC_1 1.28429 23 A6-M-B5-C5 HPLC_1 1.38 413 24 A6-M-B6-C5 HPLC_1 1.15 351 25A1-M-B5-C5 HPLC_1 1.49 461 26 A1-M-B6-C5 HPLC_1 1.28 399 27 A5-M-B5-C5HPLC_1 1.54 475 28 A5-M-B6-C5 HPLC_1 1.34 413 29 A8-M-B5-C5 HPLC_1 1.34443 30 A8-M-B6-C5 HPLC_1 1.11 381 31 A2-M-B5-C5 HPLC_1 1.36 411 32A2-M-B6-C5 HPLC_1 1.13 349

Preparation of A3-M-B1-C2 Step 8.5: Capping with Sulfonyl ChlorideDerivatives

To the resin of step (8.3) (0.11 g, corresponding to 0.077 mmol) in DCM(1 ml) it was added pyridine (0.030 g, 0.385 mmol), DMAP (0.001 g,0.0077 mmol) and methane sulfonyl chloride (group —SO₂R^(a)corresponding to fragment B1 of table II, 0.044 g, 0.385 mmol). Thereaction mixture was shaken at room temperature for 20 hours and thenthe resin was isolated by filtration. The resin was washed sequentiallywith DMF (1 ml), DCM (1 ml), DMF (1 ml), DCM (1 ml), MeOH (1 ml), water(1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml),TBME (1 ml×2) and then air dried. The product was cleaved from the resin[60% TFA/DCM, 3×(3×0.5 ml)] to give an off white solid (0.024 g, 83%)corresponding to compound A3-M-B1-C2 (see entry 33 of table V below).

LCMS (HPLC_(—)1): m/z 377 [M+H]⁺ @ r.t. 1.12 min (97.5% by ELSdetection).

Following the procedure described in example 8 and by using any properreactant as per the process of the invention that is, by supporting anysuitable amine onto the resin, by functionalizing position 1 of theazaindole moiety with any suitable reactant, by sulfonylating the aminofunction in position 5 of the azaindole moiety with any suitablesulfonyl chloride derivative and by finally carrying out resin cleavage,the following compounds of table V were also prepared.

TABLE V HPLC r.t. Entry Compound method (min) [M + H]⁺ 33 A3-M-B1-C2HPLC_1 1.12 377 34 A3-M-B4-C2 HPLC_1 1.3 439 35 A4-M-B1-C2 HPLC_1 0.9311 36 A4-M-B4-C2 HPLC_1 1.14 373 37 A7-M-B1-C2 HPLC_1 1.09 389 38A7-M-B4-C2 HPLC_1 1.28 451 39 A6-M-B1-C2 HPLC_1 0.91 311 40 A6-M-B4-C2HPLC_1 1.14 373 41 A1-M-B1-C2 HPLC_1 1.08 359 42 A1-M-B4-C2 HPLC_1 1.28421 43 A5-M-B1-C2 HPLC_1 1.17 373 44 A5-M-B4-C2 HPLC_1 1.34 435 45A8-M-B1-C2 HPLC_1 0.89 341 46 A8-M-B4-C2 HPLC_1 1.1 403 47 A2-M-B1-C2HPLC_1 0.89 309 48 A3-M-B1-C5 HPLC_1 1.37 453 49 A3-M-B4-C5 HPLC_1 1.51515 50 A4-M-B1-C5 HPLC_1 1.24 387 51 A4-M-B4-C5 HPLC_1 1.41 449 52A7-M-B1-C5 HPLC_1 1.35 465 53 A7-M-B4-C5 HPLC_1 1.49 527 54 A6-M-B1-C5HPLC_1 1.23 387 55 A6-M-B4-C5 HPLC_1 1.4 449 56 A1-M-B1-C5 HPLC_1 1.35435 57 A1-M-B4-C5 HPLC_1 1.49 497 58 A5-M-B1-C5 HPLC_1 1.41 449 59A5-M-B4-C5 HPLC_1 1.54 511 60 A8-M-B1-C5 HPLC_1 1.19 417 61 A8-M-B4-C5HPLC_1 1.37 479 62 A2-M-B1-C5 HPLC_1 1.21 385 63 A2-M-B4-C5 HPLC_1 1.38447

Step 8.6: Phenylcarbamate (and Bis-Phenylcarbamate) Formation

To the resin of step (8.3) (0.25 g, corresponding to 0.19 mmol) in DCM(10 ml) it was added triethylamine (0.39 g, 3.85 mmol) and phenylchloroformate (0.603 g, 3.85 mmol). The reaction mixture was shaken atroom temperature for 20 hours and then the resin was isolated byfiltration. The resin was washed sequentially with DMF (10 ml), DCM (10ml), DMF (10 ml), DCM (10 ml), MeOH (10 ml), DCM (10 ml), MeOH (10 ml),DCM (10 ml), MeOH (10 ml), TBME (10 ml×2) and dried in vacuo to give thecorresponding resin bound azaindole (0.275 g) which was further reactedaccording to the following step.

Preparation of A3-M-B9-C2 Step 8.7: Formation of Ureido Derivatives

To the resin of step (8.6) (0.11 g, corresponding to 0.077 mmol) in DCM(1 ml) it was added piperidine (group —CONR^(a)R^(b) corresponding tofragment B9 of table II, 0.131 g, 1.54 mmol). The reaction mixture wasshaken at room temperature for 72 hours and then the resin was isolatedby filtration. The resin was washed sequentially with DMF (1 ml), DCM (1DMF (1 DCM (1 ml), MeOH (1 ml), water (1 ml), MeOH (1 ml), DCM (1 ml),MeOH (1 ml), DCM (1 ml), MeOH (1 ml), TBME (1 ml×2) and then air dried.The product was cleaved from the resin (60% TFA/DCM, 3×(3×0.5 ml)) togive an off white solid (0.027 g, 87%) corresponding to compoundA3-M-B9-C2 (see entry 64 of table VI below).

LCMS (HPLC_(—)1): m/z 410 [M+H]⁺ @ r.t. 1.21 min (86% by ELS detection).

Following the procedure described in example 8 and by using any properreactant as per the process of the invention, that is by supporting anysuitable amine onto the resin, by functionalizing position 1 of theazaindole moiety with any suitable reactant, by preparing the carbamatederivative in position 5 of the azaindole moiety, by converting it intothe corresponding ureido derivative through reaction with any suitableamine and by finally carrying out resin cleavage, the followingcompounds of table VI were also prepared.

TABLE VI HPLC r.t. Entry Compound method (min) [M + H]⁺ 64 A3-M-B9-C2HPLC_1 1.21 410 65 A3-M-B10-C2 HPLC_1 1.15 384 66 A4-M-B10-C2 HPLC_10.95 318 67 A1-M-B10-C2 HPLC_1 1.12 366 68 A5-M-B10-C2 HPLC_1 1.19 38069 A3-M-B9-C5 HPLC_1 1.44 486 70 A7-M-B9-C5 HPLC_1 1.42 498 71A1-M-B9-C5 HPLC_1 1.42 468 72 A1-M-B10-C5 HPLC_1 1.36 442

Example 9 Step 9.1: Loading of the Azaindole Scaffold onto Rink Resin

To the Rink resin (corresponding to fragment A9 of table I, 11 g, 0.85mmol/g, 9.35 mmol) in anhydrous DMF (15 ml),5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (2.9 g, 14.03 mmol),TBTU (4.5 g, 14.03 mmol) and DIPEA (3.62 g, 28.05 mmol) were added. Thereaction mixture was shaken at room temperature for 20 hours and thenthe resin was isolated by filtration. The resin was washed sequentiallywith DMF (25 ml), DCM (25 ml), DMF (25 ml), DCM (25 ml), MeOH (25 ml),DCM (25 ml), MeOH (25 ml), DCM (25 ml), MeOH (25 ml), TBME (25 ml×2) anddried in vacuo to give the resin bound 7-azaindole (12.5 g). 0.01 g ofthe resin were cleaved (1 ml of 40% TFA/DCM) to give an off-white solid(0.0014 mg, 82%).

LCMS (HPLC_(—)1): m/z 207 [M+H]⁺ @ r.t. 0.79 min (89% by ELS detection).

Step 9.2: N-Alkylation of the Resin Bound 7-Azaindole

To the resin of step (9.1) (1.6 g, corresponding to 1.36 mmol) inanhydrous DCM (20 ml), BTPP (1.278 g, 4.08 mmol) and iodomethane (groupR₂ corresponding to fragment C2 of table III, 1.938 g, 13.6 mmol) wereadded. The reaction mixture was shaken at room temperature for 20 hoursand then the resin was isolated by filtration. The resin was washedsequentially with DMF (20 ml), DCM (20 ml), DMF (20 ml), DCM (20 ml),MeOH (20 ml), DCM (20 ml), MeOH (20 ml), DCM (20 ml), MeOH (20 ml), TBME(20 ml×2) and dried in vacuo to give the resin boundN-alkylated-7-azaindole (1.8 g). 0.01 g of the resin were cleaved (1 mlof 40% TFA/DCM) to give an off-white solid (0.0015 g, 83%).

LCMS: m/z 221 [M+H]⁺ and 262 [M+MeCN+H]⁺ @ r.t. 1.35 min (65% @ 215 nm).

Step 9.3: Reduction of the Nitro Group

To the resin of step (9.2) (1.6 g) in NMP (20 ml) it was added tin(II)chloride dihydrate (3.1 g, 13.6 mmol). The reaction mixture was shakenat room temperature for 20 hours and then the resin was isolated byfiltration. The resin was washed sequentially with DMF (20 ml), DCM (20ml), DMF (20 ml), DCM (20 ml), MeOH (20 ml), water (20 ml), MeOH (20ml), DCM (20 ml), MeOH (20 ml), DCM (20 ml), MeOH (20 ml), TBME (20ml×2) and dried in vacuo to give the resin bound 5-amino-7-azaindole(0.825 g). 0.01 g of the resin were cleaved (1 ml of 40% TFA/DCM) togive an off-white solid (0.0012 g, 75%).

LCMS (HPLC_(—)1): m/z 191 [M+H]⁺ @ r.t. 0.59 min (100% by ELSdetection).

The above resin bound azaindole was further reacted according to thealternative steps below so as to get carboxamido, sulfonamido and ureidoderivatives.

Preparation of A9-M-B5-C2 Step 9.4: Capping with Acid ChlorideDerivatives

To the resin of step (9.3) (0.11 g, corresponding to 0.085 mmol) in DCM(1 ml) it was added Hunig's base (0.055 g, 0.425 mmol) followed bybenzoyl chloride (group —COR^(a) corresponding to fragment B5 of tableII, 0.060 g, 0.425 mmol). The reaction mixture was shaken at roomtemperature for 20 hours and then the resin was isolated by filtration.The resin was washed sequentially with DMF (1 ml), DCM (1 ml), DMF (1ml), DCM (1 ml), MeOH (1 ml), water (1 ml), MeOH (1 ml), DCM (1 ml),MeOH (1 ml), DCM (1 ml), MeOH (1 ml), TBME (1 ml×2) and then air dried.The resin was shaken in acetonitrile/ammonia solution (1 ml, 4:1) for 4hours and then isolated by filtration. The resin was washed sequentiallywith DMF (1 ml), DCM (1 ml), DMF (1 ml), DCM (1 ml), MeOH (1 ml), water(1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml),TBME (1 ml×2) and then air dried. The product was cleaved from the resin(40% TFA/DCM, 3×0.5 ml) to give an off white solid (0.017 g, 68%)corresponding to compound A9-M-B5-C2 (see entry 3 of table VII below).

LCMS (HPLC_(—)1): m/z 295 [M+H]⁺ @ r.t. 0.92 min (88% by ELS detection).

By working in an analogous way and by using any suitable startingmaterial and reactant of the process, the following compounds of tableVII were also prepared.

TABLE VII HPLC r.t. Entry Compound method (min) [M + H]⁺ 1 A9-M-B5-C1HPLC_1 1.09 335 2 A9-M-B7-C1 HPLC_1 1.17 349 3 A9-M-B5-C2 HPLC_1 0.92295 4 A9-M-B7-C2 HPLC_1 1.02 309 5 A9-M-B5-C3 HPLC_1 0.99 309 6A9-M-B7-C3 HPLC_1 1.07 323 7 A9-M-B8-C3 HPLC_1 0.84 273 8 A9-M-B5-C4HPLC_1 1.03 321 9 A9-M-B5-C5 HPLC_1 1.2 371 10 A9-M-B5-C6 HPLC_1 1.45427 11 A9-M-B7-C6 HPLC_1 1.51 441 12 A9-M-B8-C6 HPLC_1 1.35 391 13A9-M-B5-C7 HPLC_1 1.27 385 14 A9-M-B6-C7 HPLC_1 1.05 323 15 A9-M-B8-C7HPLC_1 1.15 349 16 A9-M-B5-C8 HPLC_1 1.34 439 17 A9-M-B7-C8 HPLC_1 1.41453 18 A9-M-B8-C8 HPLC_1 1.24 403 19 A9-M-B13-C2 HPLC_1 0.21 191 20A9-M-B13-C5 HPLC_1 0.86 267 21 A9-M-B13-C6 HPLC_1 1.14 323 22A9-M-B13-C8 HPLC_1 1.04 335

Preparation of A9-M-B4-C2 Step 9.5: Capping with Sulfonyl ChlorideDerivatives

To the resin of step (9.3) (0.11 g, corresponding to 0.085 mmol) in DCM(1 ml), pyridine (0.034 g, 0.425 mmol), DMAP (0.001 g, 0.0085 mmol) andbenzene sulfonyl chloride (group —SO2Ra corresponding to fragment B4 oftable III, 0.075 g, 0.385 mmol) were added. The reaction mixture wasshaken at room temperature for 20 hours and then the resin was isolatedby filtration. The resin was washed sequentially with DMF (1 ml), DCM (1ml), DMF (1 ml), DCM (1 ml), MeOH (1 ml), water (1 ml), MeOH (1 ml), DCM(1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), TBME (1 ml×2) and then airdried. The product was cleaved from the resin (40% TFA/DCM, 3×0.5 ml) togive an off white solid (0.022 g, 80%) corresponding to compoundA9-M-B4-C2 (see entry 24 of table VIII below).

LCMS (HPLC_(—)1): m/z 331 [M+H]⁺ @ r.t. 0.96 min (81% by ELS detection).

By working in an analogous way and by using any suitable startingmaterial and reactant of the process, the following compounds of tableVIII were also prepared.

TABLE VIII HPLC r.t. Entry Compound method (min) [M + H]⁺ 23 A9-M-B1-C1HPLC_1 0.92 309 24 A9-M-B4-C2 HPLC_1 0.96 331 25 A9-M-B3-C3 HPLC_1 0.83297 26 A9-M-B1-C4 HPLC_1 0.85 295 27 A9-M-B3-C4 HPLC_1 0.89 309 28A9-M-B1-C5 HPLC_1 1.04 345 29 A9-M-B3-C5 HPLC_1 1.08 359 30 A9-M-B4-C5HPLC_1 1.23 407 31 A9-M-B2-C6 HPLC_1 1.52 477 32 A9-M-B3-C6 HPLC_1 1.36415 33 A9-M-B4-C6 HPLC_1 1.47 463 34 A9-M-B3-C7 HPLC_1 1.16 373 35A9-M-B1-C8 HPLC_1 1.21 413 36 A9-M-B2-C8 HPLC_1 1.41 489 37 A9-M-B3-C8HPLC_1 1.24 427 38 A9-M-B4-C8 HPLC_1 1.36 475

Step 9.6: Phenyl Carbamate (and Bis Phenyl Carbamate) Formation

To the resin of step (9.3) (0.60 g, corresponding to 0.51 mmol) in DCM(10 ml), triethylamine (1.03 g, 10.2 mmol) and phenyl chloroformate(1.597 g, 10.2 mmol) were added. The reaction mixture was shaken at roomtemperature for 20 hours and then the resin was isolated by filtration.The resin was washed sequentially with DMF (10 ml), DCM (10 ml), DMF (10ml), DCM (10 ml), MeOH (10 ml), DCM (10 ml), MeOH (10 ml), DCM (10 ml),MeOH (10 ml), TBME (10 ml×2) and dried in vacuo to give the resin bound7-azaindole (0.65 g). 0.01 g of the resin were cleaved (1 ml of 40%TFA/DCM) to give an off-white solid (0.001 g, 69%).

LCMS (HPLC_(—)1) (mono and bis phenyl carbamates observed): m/z 311[M+H]⁺ @ r.t. 1.03 min (77% by ELS detection) and m/z 431 [M+H]⁺ @ r.t.1.31 min (12% by ELS detection).

Preparation of A9-M-B9-C2 Step 9.7: Formation of Ureido Derivatives

To the resin of step (9.6) (0.11 g, corresponding to 0.085 mmol) in DCM(1 ml) it was added piperidine (group —CONR^(a)R^(b) corresponding tofragment B9 of table II, 0.143 g, 1.7 mmol). The reaction mixture wasshaken at room temperature for 72 hours and then the resin was isolatedby filtration. The resin was washed sequentially with DMF (1 ml), DCM (1ml), DMF (1 ml), DCM (1 ml), MeOH (1 ml), water (1 ml), MeOH (1 ml), DCM(1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), TBME (1 ml×2) and then airdried. The product was cleaved from the resin (40% TFA/DCM, 3×0.5 ml) togive an off white solid (0.020 g, 79%) corresponding to compoundA9-M-B9-C2 (see entry 40 of table IX below).

LCMS (HPLC_(—)1): m/z 302 [M+H]⁺ @ r.t. 0.86 min (91% by ELS detection).

By working in an analogous way and by using any suitable startingmaterial and reactant of the process, the following compounds of tableIX were also prepared.

TABLE IX HPLC r.t. Entry Compound method (min) [M + H]⁺ 39 A9-M-B9-C1HPLC_1 1.02 342 40 A9-M-B9-C2 HPLC_1 0.86 302 41 A9-M-B10-C2 HPLC_1 0.79276 42 A9-M-B11-C2 HPLC_1 0.95 324 43 A9-M-B9-C3 HPLC_1 0.92 316 44A9-M-B10-C3 HPLC_1 0.84 290 45 A9-M-B11-C3 HPLC_1 0.99 338 46 A9-M-B9-C4HPLC_1 0.96 328 47 A9-M-B10-C4 HPLC_1 0.89 302 48 A9-M-B11-C4 HPLC_11.04 350 49 A9-M-B9-C5 HPLC_1 1.13 378 50 A9-M-B12-C5 HPLC_1 0.88 379 51A9-M-B10-C5 HPLC_1 1.07 352 52 A9-M-B11-C5 HPLC_1 1.19 400 53 A9-M-B9-C6HPLC_1 1.39 434 54 A9-M-B12-C6 HPLC_1 1.14 435 55 A9-M-B10-C6 HPLC_11.34 408 56 A9-M-B11-C6 HPLC_1 1.42 456 57 A9-M-B9-C7 HPLC_1 1.2 392 58A9-M-B12-C7 HPLC_1 0.95 393 59 A9-M-B10-C7 HPLC_1 1.14 366 60A9-M-B11-C7 HPLC_1 1.25 414 61 A9-M-B9-C8 HPLC_1 1.29 446 62 A9-M-B12-C8HPLC_1 1.04 447 63 A9-M-B10-C8 HPLC_1 1.23 420 64 A9-M-B11-C8 HPLC_11.33 468

Example 10 Step 10.1: Loading of the Azaindole Scaffold onto the Resin

To the AMEBA II resin (0.1 g, 1 mmol/g, 0.1 mmol) in DCM/DMF (1:1, 2ml), 1-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (3eq), DIC (1.5 eq) DMAP (0.5 eq) and DIPEA (1 eq) were added. Thereaction mixture was shaken at room temperature for 20 hours and thenthe resin was isolated by filtration. The resin was washed sequentiallywith DMF (2 ml), DCM (2 ml), DMF (2 ml), DCM (2 ml), MeOH (2 ml), DCM (2ml), MeOH (2 ml), DCM (2 ml), MeOH (2 ml), DCM (2 ml) and dried in vacuoto give the resin bound 7-azaindole.

Step 10.2: Reduction of the Nitro Group

To the resin of step (10.1) (0.1 g, 1 mmol/g, 0.1 mmol) in NMP (2 ml),it was added tin(II) chloride dihydrate (10 eq). The reaction mixturewas shaken at room temperature for 20 hours and then the resin wasisolated by filtration. The resin was washed sequentially with DMF (5ml), DCM (5 ml), DMF (5 ml), DCM (5 ml), MeOH (5 ml), water (5 ml), MeOH(5 ml), DCM (5 ml), MeOH (5 ml), DCM (5 ml), MeOH (5 ml), DCM (5 ml) anddried in vacuo to give the resin bound 5-amino-7-azaindole. 0.01 g ofthe resin were cleaved (1 ml of 20% TFA/DCM for 20 minutes) to give thecorresponding amine.

LCMS (HPLC_(—)2): m/z 323 [M+H]⁺, r.t. 5.2 min.

Preparation of A1-M-B6-C9 Step 10.3: Capping with Acyl ChlorideDerivatives

To the resin of step (10.2) (0.1 g, corresponding to 0.1 mmol) in DCM (1ml) it was added Hunig's base (5 eq) followed by acetyl chloride (group—COR^(a) corresponding to fragment B6 of table II, 5 eq). The reactionmixture was shaken at room temperature for 20 hours and then the resinwas isolated by filtration. The resin was washed sequentially with DMF(2 ml), DCM (2 ml), DMF (2 ml), DCM (2 ml), MeOH (2 ml), water (2 ml),MeOH (2 ml), DCM (2 ml), MeOH (2 ml), DCM (2 ml), MeOH (2 ml), DCM (1ml×2) and then dried. The resin was shaken in acetonitrile/ammoniasolution (1 ml, 4:1) for 4 hours and then isolated by filtration. Thecompound5-(acetylamino)-N-benzyl-1-tert-butyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide,having code A1-M-B6-C9, was cleaved from the resin [20% TFA/DCM,3×(3×0.5 ml)].

LCMS (HPLC_(—)2): m/z 365 [M+H]⁺, r.t. 5.4 min.

Preparation of A1-M-B14-C9 Step 10.4: Capping with Sulfonyl ChlorideDerivatives

To the resin of step (10.2) (0.1 g, corresponding to 0.1 mmol) in DCM (1ml), DIPEA (5 eq), DMAP (0.1 eq) and 4-(acetylamino)benzenesulfonylchloride (group —SO₂R^(a) corresponding to fragment B14 of table II, 5eq) were added. The reaction mixture was shaken at room temperature for20 hours and then the resin was isolated by filtration. The resin waswashed sequentially with DMF (2 ml), DCM (2 ml), DMF (2 ml), DCM (2 ml),MeOH (2 ml), water (2 ml), MeOH (2 ml), DCM (2 ml), MeOH (2 ml), DCM (2ml), MeOH (2 ml), DCM (1 ml×2) and then dried under vacuum. The compound5-({[4-(acetylamino)phenyl]sulfonyl}amino)-N-benzyl-1-tert-butyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide,having code A1-M-B14-C9, was cleaved from the resin (20% TFA/DCM,3×(3×0.5 ml).

LCMS (HPLC_(—)2): m/z 520 [M+H]⁺, r.t. 6.0 min.

Preparation of A1-M-B15-C9 Step 10.5: Capping with IsocyanateDerivatives

To the resin of step (10.3) (0.1 g, corresponding to 0.1 mmol) in DCM (1ml), it was added butylisocyanate (group —CONR^(a)R^(b) corresponding tofragment B15 of table II, 10 eq). The reaction mixture was shaken atroom temperature for 48 hours and then the resin was isolated byfiltration. The resin was washed sequentially with DMF (2 ml), DCM (2ml), DMF (2 ml), DCM (2 ml), MeOH (2 ml), water (2 ml), MeOH (2 ml), DCM(2 ml), MeOH (2 ml), DCM (2 ml), MeOH (2 ml), DCM (1 ml×2) and thendried under vacuum. The compoundN-benzyl-1-tert-butyl-5-{[(butylamino)carbonyl]amino}-1H-pyrrolo[2,3-b]pyridine-3-carboxamide,having code A1-M-B15-C9, was cleaved from the resin 20% TFA/DCM,3×(3×0.5 ml).

LCMS (HPLC_(—)2): m/z 422 [M+H]⁺, r.t. 6.5 min.

1. A method for treating conditions or diseases caused by and/orassociated with an altered protein kinase activity which comprisesadministering to a mammal in need thereof an effective amount of apyrrolo[2,3-b]pyridine represented by formula (I)

wherein R is —R^(a), —COR^(a), —CONR^(a)R^(b), —SO₂R^(a) or —COOR^(a);R₁ is —NR^(c)R^(d) or —OR^(c); wherein R^(a), R^(b), R^(c) and R^(d),are the same or different, and are each independently hydrogen or agroup optionally further substituted, selected from straight or branchedC₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight or branchedC₂-C₆ alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, aryl or arylC₁-C₆ alkyl, or heterocycle or heterocycle C₁-C₆ alkyl or, takentogether with the nitrogen atom to which they are bonded, either R^(a)and R^(b) as well as R^(c) and R^(d) may form an optionally substituted4 to 7 membered heterocycle, optionally containing one additionalheteroatom or heteroatomic group selected from S, O, N and NH; R₂ is agroup, optionally further substituted, selected from straight orbranched C₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight orbranched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, arylor aryl C₁-C₆ alkyl, or heterocycle or heterocycle C₁-C₆ alkyl; orisomers, tautomers, carriers, metabolites, prodrugs, andpharmaceutically acceptable salts thereof.
 2. The method according toclaim 1 wherein the disease caused by and/or associated with an alteredprotein kinase activity is a cell proliferative disorder selected fromthe group consisting of cancer, Alzheimer's disease, viral infections,auto-immune diseases and neurodegenerative disorders.
 3. The methodaccording to claim 2 wherein the cancer is selected from the groupconsisting of carcinoma, squamous cell carcinoma, hematopoietic tumoursof myeloid or lymphoid lineage, tumours of mesenchymal origin, tumoursof the central and peripheral nervous system, melanoma, seminoma,teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma,thyroid follicular cancer, and Kaposi's sarcoma.
 4. The method accordingto claim 1 wherein the cell proliferative disorder is selected from thegroup consisting of benign prostate hyperplasia, familial adenomatosispolyposis, neuro-fibromatosis, psoriasis, vascular smooth cellproliferation associated with atherosclerosis, pulmonary fibrosis,arthritis, glomerulonephritis and post-surgical stenosis and restenosis.5. A method for inhibiting tumour angiogenesis or metastasis in a mammalwhich comprises administering thereto an effective amount of a compoundrepresented by the formula

wherein R is —R^(a), —COR^(a), —CONR^(a)R^(b), —SO₂R^(a) or —COOR^(a);R₁ is —NR^(c)R^(d) or —OR^(c); wherein R^(a), R^(b), R^(c) and R^(d),are the same or different, and are each independently hydrogen or agroup optionally further substituted, selected from straight or branchedC₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight or branchedC₂-C₆ alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, aryl or arylC₁-C₆ alkyl, or heterocycle or heterocycle C₁-C₆ alkyl or, takentogether with the nitrogen atom to which they are bonded, either R^(a)and R^(b) as well as R^(c) and R^(d) may form an optionally substituted4 to 7 membered heterocycle, optionally containing one additionalheteroatom or heteroatomic group selected from S, O, N and NH; R₂ is agroup, optionally further substituted, selected from straight orbranched C₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight orbranched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, arylor aryl C₁-C₆ alkyl, or heterocycle or heterocycle C₁-C₆ alkyl; orisomers, tautomers, carriers, metabolites, prodrugs, andpharmaceutically acceptable salts thereof.
 6. The method according toclaim 1 in which the condition caused by or associated with an alteredprotein kinase activity is organ transplant rejection or host versusgraft disease.
 7. A method for treating or preventing ofradiotherapy-induced or chemotherapy-induced alopecia in a mammal whichcomprises administering thereto an effective amount of a compound of theformula

wherein R is —R^(a), —COR^(a), —CONR^(a)R^(b), —SO₂R^(a) or —COOR^(a);R₁ is —NR^(c)R^(d) or —OR^(c); wherein R^(a), R^(b), R^(c) and R^(d),are the same or different, and are each independently hydrogen or agroup optionally further substituted, selected from straight or branchedC₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight or branchedC₂-C₆ alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, aryl or arylC₁-C₆ alkyl, or heterocycle or heterocycle C₁-C₆ alkyl or, takentogether with the nitrogen atom to which they are bonded, either R^(a)and R^(b) as well as R^(c) and R^(d) may form an optionally substituted4 to 7 membered heterocycle, optionally containing one additionalheteroatom or heteroatomic group selected from S, O, N and NH; R₂ is agroup, optionally further substituted, selected from straight orbranched C₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight orbranched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, arylor aryl C₁-C₆ alkyl, or heterocycle or heterocycle C₁-C₆ alkyl; orisomers, tautomers, carriers, metabolites, prodrugs, andpharmaceutically acceptable salts thereof.
 8. The method according toclaim 1 further comprising subjecting the mammal in need thereof to aradiation therapy or chemotherapy regimen in combination with at leastone cytostatic or cytotoxic agent.
 9. The method according to claim 1wherein the mammal in need thereof is a human.
 10. A method forinhibiting protein kinase activity which comprises contacting the saidkinase with an effective amount of a compound of formula (I) having theformula

wherein R is —R^(a), —COR^(a), —CONR^(a)R^(b), —SO₂R^(a) or —COOR^(a);R₁ is —NR^(c)R^(d) or —OR^(c); wherein R^(a), R^(b), R^(c) and R^(d),are the same or different, and are each independently hydrogen or agroup optionally further substituted, selected from straight or branchedC₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight or branchedC₂-C₆ alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, aryl or arylC₁-C₆ alkyl, or heterocycle or heterocycle C₁-C₆ alkyl or, takentogether with the nitrogen atom to which they are bonded, either R^(a)and R^(b) as well as R^(c) and R^(d) may form an optionally substituted4 to 7 membered heterocycle, optionally containing one additionalheteroatom or heteroatomic group selected from S, O, N and NH; R₂ is agroup, optionally further substituted, selected from straight orbranched C₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight orbranched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, arylor aryl C₁-C₆ alkyl, or heterocycle or heterocycle C₁-C₆ alkyl; orisomers, tautomers, carriers, metabolites, prodrugs, andpharmaceutically acceptable salts thereof. 11-20. (canceled)
 21. Alibrary comprised of two or more compounds of formula (I)

wherein R is selected from the group consisting of —R^(a), —COR^(a),—CONR^(a)R^(b), —SO₂R^(a) or —COOR^(a); R₁ is a group —NR^(c)R^(d) or—OR^(c); wherein R^(a), R^(b), R^(c) and R^(d), are the same ordifferent, and are each independently hydrogen or a group optionallyfurther substituted, selected from straight or branched C₁-C₆ alkyl,straight or branched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl,C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, aryl, aryl C₁-C₆ alkyl, orheterocycle or heterocycle C₁-C₆-alkyl or, taken together with thenitrogen atom to which they are bonded, either R^(a) and R^(b) as wellas R^(c) and R^(d) may form an optionally substituted 4 to 7 memberedheterocycle, optionally containing one additional heteroatom orheteroatomic group selected from S, O, N and NH; R₂ is a group,optionally further substituted, selected from straight or branched C₁-C₆alkyl, straight or branched C₂-C₆ alkenyl, straight or branched C₂-C₆alkynyl, C₃-C₆ cycloalkyl or cycloalkyl C₁-C₆ alkyl, aryl or aryl C₁-C₆alkyl, or heterocycle or heterocycle C₁-C₆ alkyl; or isomers, tautomers,carriers, metabolites, prodrugs, and pharmaceutically acceptable saltsthereof.
 22. The library according to claim 21 wherein R₁ is a group—NR^(c)R^(d) and R^(c) and R^(d) are both hydrogen atoms or one of themis a hydrogen atom and the remaining one of R^(c) or R^(d) is alkyl oralkenyl group, or an optionally substituted aryl or arylalkyl group. 23.The library according to claim 21 wherein R is hydrogen or a group—SO₂R^(a) wherein R^(a) is a straight or branched alkyl or optionallysubstituted aryl or arylalkyl group.
 24. The library according to claim21 wherein R is a group —COR^(a) wherein R^(a) is a straight or branchedalkyl, cycloalkyl or optionally substituted aryl or arylalkyl group. 25.The library according to claim 21 wherein R is —CONR^(a)R^(b) whereinone of R^(a) and R^(b) is hydrogen and the other of R^(a) and R^(b) is astraight or branched alkyl or optionally substituted aryl or arylalkylgroup.
 26. The library according to claim 21 wherein R is—CONR^(a)R^(b), R^(a) and R^(b) form, together with the nitrogen atom towhich they are bonded, an optionally substituted 6 membered heterocyclicring.
 27. The library according to claim 21 wherein R₂ is alkyl, alkenylgroup, cycloalkyl, cycloalkyl-alkyl or an optionally substituted aryl orarylalkyl group.
 28. The library according to claim 21 wherein thecompound in the library is a compound listed in Table IV, V, VI, VII,VIII or IX.
 29. A pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I)

wherein R is selected from the group consisting of —R^(a), —COR^(a),—CONR^(a)R^(b), —SO₂R^(a) and —COOR^(a); R₁ is —NR^(c)R^(d) or —OR^(c);wherein R^(a), R^(b), R^(c) and R^(d) are the same or different and areeach independently hydrogen or a group, optionally further substituted,which is straight or branched C₁-C₆ alkyl, straight or branched C₂-C₆alkenyl, straight or branched C₁-C₆ alkynyl, C₃-C₆ cycloalkyl,C₃-C₆cycloalkyl C₁-C₆ alkyl, an aryl, aryl C₁-C₆ alkyl, a heterocycleand heterocycle C₁-C₆ alkyl or, taken together with the nitrogen atom towhich they are bonded, R^(a) and R^(b) as well as R^(c) and R^(d) form a1,3-dioxolane, pyran, pyrrolidine, pyrroline, imidazoline,imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine,morpholine, tetrahydrofuran, hexamethyleneimine, 1,4-hexahydrodiazepineor azetidine group; R₂ is a group, optionally further substituted,selected from the group consisting of straight or branched C₁-C₆ alkyl,straight or branched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl C₁-C₆ alkyl, aryl, aryl C₁-C₆ alkyl,heterocycle and heterocycle C₁-C₆ alkyl; wherein any of R^(a), R^(b),R^(c), R^(d) or R₂ is independently optionally substituted by halogen,nitro, oxo groups, carboxy, cyano, alkyl, perfluoroalkyl, alkenyl,cycloalkyl, cycloalkenyl, aryl, heterocyclyl, amino groups,carbonylamino groups, hydroxy groups, carbonyl groups or sulfuratedgroups; wherein said aryl is selected from the group consisting ofphenyl, indanyl, biphenyl, α- or β-naphthyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolyl, imidazolyl, imidazopyridyl,1,2-methylenedioxyphenyl, thiazolyl, isothiazolyl, pyrrolyl,pyrrolyl-phenyl, furyl, phenyl-furyl, benzotetrahydrofuranyl, oxazolyl,isoxazolyl, pyrazolyl, chromenyl, thienyl, benzothienyl, isoindolinyl,benzoimidazolyl, quinolin, isoquinolinyl, quinoxalinyl, benzofurazanyl,1,2,3-triazolyl and 1-phenyl-1,2,3-triazolyl; wherein said heterocycleis selected from the group consisting of 1,3-dioxolane, pyran,pyrrolidine, pyrroline, imadazoline, imidazolidine, pyrazolidine,pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran,hexamethyleneimine, 1,4-hexahydrodiazepine and azetidine, or isomers,tautomers, carriers, and pharmaceutically acceptable salts thereof and,at least, one pharmaceutically acceptable excipient, carrier and/ordiluent.
 30. The pharmaceutical composition according to claim 29further comprising one or more chemotherapeutic agents.
 31. A kitcomprising a compound according to claim 11 of formula (I)

wherein R is selected from the group consisting of —R^(a), —COR^(a),—CONR^(a)R^(b), —SO₂R^(a) and —COOR^(a); R₁ is —NR^(c)R^(d) or —OR^(c);wherein R^(a), R^(b), R^(c) and R^(d) are the same or different and areeach independently hydrogen or a group, optionally further substituted,which is straight or branched C₁-C₆ alkyl, straight or branched C₂-C₆alkenyl, straight or branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkyl C₁-C₆ alkyl, an aryl, aryl C₁-C₆ alkyl, a heterocycle andheterocycle C₁-C₆ alkyl or, taken together with the nitrogen atom towhich they are bonded, R^(a) and R^(b) as well as R^(c) and R^(d) form a1,3-dioxolane, pyran, pyrrolidine, pyrroline, imidazoline,imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine,morpholine, tetrahydrofuran, hexamethyleneimine, 1,4-hexahydrodiazepineor azetidine group; R₂ is a group, optionally further substituted,selected from the group consisting of straight or branched C₁-C₆ alkyl,straight or branched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl C₁-C₆ alkyl, aryl, aryl C₁-C₆ alkyl,heterocycle and heterocycle C₁-C₆ alkyl; wherein any of R^(a), R^(b),R^(c), R^(d) or R₂ is independently optionally substituted by halogen,nitro, oxo groups, carboxy, cyano, alkyl, perfluoroalkyl, alkenyl,cycloalkyl, cycloalkenyl, aryl, heterocyclyl, amino groups,carbonylamino groups hydroxy groups, carbonyl groups or sulfuratedgroups; wherein said aryl is selected from the group consisting ofphenyl, indanyl, biphenyl, α- or β-naphthyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolyl, imidazolyl, imidazopyridyl,1,2-methylenedioxyphenyl, thiazolyl, isothiazolyl, pyrrolyl,pyrrolyl-phenyl, furyl, phenyl-furyl, benzotetrahydrofuranyl, oxazolyl,isoxazolyl, pyrazolyl, chromenyl, thienyl, benzothienyl, isoindolinyl,benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl,benzofurazanyl, 1,2,3-triazolyl and 1-phenyl-1,2,3-triazolyl; whereinsaid heterocycle is selected from the group consisting of 1,3-dioxolane,pyran, pyrrolidine, pyrroline, imadazoline, imidazolidine, pyrazolidine,pyrazoline, piperidine, piperazine, morpholine tetrahydrofuran,1,4-hexahydrodiazepine and azetidine; or isomers, tautomers, carriers,and pharmaceutically acceptable salts thereof and, at least optionallyassociated with a pharmaceutical excipient or carrier and/or diluent,and one or more chemotherapeutic agents.